JPS6011490A - Beta-lactam derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I {R is (substituted)thiazolyl, or furyl; R1 is H, or halogen R2 is halogen, lower alkoxycarbonyl, OH, or carboxymethylmercapto; Y is group shown by the formula II [R3 is -R5, -S-R<5> (R5 is nitrogen-containing heterocylic residue); R4 is H, salt-forming cation, or carboxylic acid-protecting group]; with the proviso that when R1 is H and R2 is halogen, Y may be further group shown by the formula III} and its salt. EXAMPLE:A 7-[2-chloromethylene-2-( 2-aminothiazol-4-yl )acetamido]-3-[8-methyl- tetrazolo( 1, 5-b )pyridazi#ne-6-yl]thiomethyl-3-cephem-4-carboxylic acid shown by the formula IV. USE:An antibacterial agent. Showing improved antibacterial activity espectially against Gram-positive bacteria and bacteria capable of producing beta-lactamase. PREPARATION:A compound shown by the formula V (reactive derivative, or salt, is reacted with an acid shown by the formula VI (reactive derivative, or salt).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel β-lactam ring-containing derivative having excellent antibacterial activity.

[Prior art]

Conventionally, penicillin and cephalosporin compounds have shown broad antibacterial activity against Durham-positive bacteria and Gram-negative bacteria.
Several semi-synthetic penicillins or cephalosporins are commercially available and are used clinically as therapeutic agents for various infectious diseases.

However, there are only a few therapeutic agents that exhibit antibacterial activity against Pseudomonas aeruginosa, Pseudomonas occidentalis, and the like, which cause clinically serious infections. Also,
These commercially available drugs are unstable against β-lactamases produced by resistant bacteria, and have drawbacks such as low antibacterial activity against drug-resistant bacteria, which is currently a clinical problem. Published by Tsuku Press 1972, E.

■, edited by Flynn, Chapter 11, W. B. Wick, "Cephalosporins and Penicillins, Chemistry and Biology" (W.
Ft, Wick [0ephalosporins
and Pencilline.

Chemistry and Biology J
, edited by E, H+F'1ynn.

Academic Press, New York
, N.Y., 1972; Chapter 11). Therefore, the search for β-lactam compounds that have antibacterial properties that are effective against such pathogenic bacteria is currently ongoing.

[Purpose of the invention]

An object of the present invention is to provide novel β-lactam derivatives having antibacterial activity superior to those previously known.

[Structure of the invention]

To summarize the present invention, the present invention relates to a new compound, which has the following general formula I: [wherein R represents a substituted or unsubstituted thiazolyl group or furyl group, and R1 is hydrogen or) Indicates an atom, R2, -, rogen atom, lower alkoxycarbonyl group, hydroxyl group or carboxymethylmercapto group,
Y is a group represented by the formula \4°-0H2-Rs (wherein
o2R4 R3 represents -R5 or -8-R6 group (where R5 means a nitrogen-containing heterocyclic residue), and R4 represents hydrogen, a salt-forming cation, or a carboxylic acid protecting group); ,R
1 may be hydrogen and R2 may be a group represented by ノ・口] or a non-toxic salt thereof.

The compound of the present invention represented by the general formula (1) will be explained in more detail.

In the compounds of the present invention, stereoisomers exist due to the carbon double bond between groups R1 and R2.

Examples of the substituent for OR in the formula include an amino group, a protected amino group, a halogen, a nitro group, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, and a lower alkylmercapto group.

R2 is a halogen atom, such as chlorine, bromine or iodine,
It represents a lower alkoxycarbonyl group such as a methquincarbonyl group or an ethoxycarbonyl group, a hydroxyl group or a carboxymethylmercapto group.

Examples of the nitrogen-containing heterocyclic residue represented by R5 include a thiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a triazinyl group, and a tetracylo[1°5-b]pyridazyl group. It will be done. Each of these terms may have a substituent.

Other groups include those commonly used in β-lactam compounds.

The compound of the present invention is a compound represented by the following general formula (1): [The group Y in the formula has the same meaning as formula (1)], or a reactive derivative thereof at the amino group, or a salt thereof. and general formula ■: [The groups R, R1 and R2 in the formula have the same meanings as in formula (1)]
It can be produced by reacting with an acid represented by the following formula, a reactive derivative of the carboxyl group of this acid, or a salt thereof.

The compound represented by the general formula (lIl) used as a raw material can be produced, for example, by reacting an R-substituted glyoxylic acid derivative with halomethylenetriphenylphosphorane.

Moreover, the acid represented by the general formula (11), which is the other raw material, is easily available industrially.

Next, embodiments of the method for producing the compound of the present invention will be described.

When reacting a compound represented by the general formula (Ill) as a reactant in the form of a free acid (or its salt), N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethercarbodiimide is usually used. , N,N'-diethylcarbodiimide, N,N'-carbonyl (2-methylimidazole), phosphoric acid trialkyl ester, polyphosphoric acid ethyl ester, phosphorus oxychloride, phosphorus trichloride, 2-chloro-1,3,2 - The reaction is preferably carried out in the presence of a dehydration condensing agent such as dioxaphosphorane or oxalyl chloride.

Further, examples of the salt of the compound represented by the general formula (III) include alkali metal salts, alkaline earth metal salts, ammonium salts, and salts with organic bases such as triethylamine and dicyclohexylamine.

As the reactive derivative of the compound of general formula (Ill), reactive derivatives commonly used in the synthesis of acid amides are used. Specific examples include acid rogides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, active acid amides, acid cyanides, active esters, and acid azides of the compound represented by the general formula (1). etc., and acid chlorides, mixed acid anhydrides and activated amides are particularly preferred.

Examples of mixed acid anhydrides include aliphatic carboxylic acids, aromatic carboxylic acids, alkyl carbonates, aralkyl carbonates, dialkyl phosphoric acids, diphenyl phosphoric acids, methanesulfone m, p
Examples of active esters include cyanomethyl esters, substituted phenyl esters, substituted benzyl esters, substituted chenyl esters, etc., and examples of active acid amides include: Examples include acid amides such as imidazole, 4-@substituted imidazole, dimethylpyrazole, triazole, tetrazole, and saccharin.

The compound represented by the general formula (It) is subjected to the reaction as a free substance, a salt thereof, or an ester thereof.

Examples of the salts of the compound represented by general formula (II) include salts with organic acids such as acetate, benzenesulfonate, tartrate, trifluoroacetate, and formate; hydrochloride; hydrobromide; Salts with inorganic acids such as sulfates and phosphates, sodium salts,
Alkali metal salts such as potassium salts, trimethylamine salts,
Salts with organic bases such as triethylamine salts and dibutylamine salts are used. Examples of the ester of the compound represented by the general formula (■) include benzhydryl ester, trichloroethyl ester, hivaloyloxymethyl ester, p-nitrobenzyl ester, and alkylsilyl ester.

This reaction is usually carried out in a solvent. As a solvent, dimethyl sulfoxide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether,
Common organic solvents that do not participate in the reaction include benzene, toluene, methylene chloride, chloroform, vinegar, ether, methyl in butyl ketone, etc., and these solvents can also be used in combination with water. The reaction can be carried out in the presence of a base. Examples of bases include inorganic groups such as caustic alkali, alkali carbonate, alkali bicarbonate, alkali acetate, trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N
- Tertiary amines such as methylmorpholine, lutidine and collidine; secondary amines such as diethylamine and dicyclohexylamine;

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.

Furthermore, the compound of the present invention represented by the general formula (1) is a compound represented by the following general formula (1): [wherein R and Y have the same meanings as in the formula (1)] and halomethinone triphenylphosphorane. Also, by the Uittich reaction with the following general formula (■): [wherein R% RI , R2 and Y are the same as in formula (1)], R5 and a different type of nuclear reagent are reacted. Furthermore, thioureas can be added to a compound represented by the following general formula (1); It can also be produced by applying (
(See specification 1 of Japanese Patent Application No. 57-45593).

The β-lactam derivative obtained by the production method described in detail above can be purified by a treatment means known per se, such as chromatography, extraction, precipitation, and recrystallization. Moreover, if necessary, it can be converted into a desired salt, ester, etc. by a method known per se.

Examples of bacteria and spirochetes on which the β-lactam derivatives and nontoxic salts thereof of the present invention effectively act include the following.

Staphylococcus, Streptococcus, Bacillus (such as Anthrax),
Corynebacterium (diphtheria, etc.), Mycobacterium (tuberculosis, etc.), Neisseria (gonococcus, etc.), Pseudomonas (pseudomonas aeruginosa, etc.), Nisierisia (Escherichia coli, etc.)
, Citrobacter-i, Salmonella, Shigella (Shigella, etc.), Klebsiella (Klebsiella pneumonia, etc.), Enterobacter, Serratia, Proteus, Vibrio (cholera, etc.), Bordetella (pertussis W, etc.) , Haemophilus (such as Haemophilus influenzae), Pursella, and Streptococcus (
soft bacteria, etc.), Clostridium, Bacteroides,
Hubbacterium, Beptococcus, Beptostrebutococcus, Bayonella, Niebacterium, Propionibacterium, Spirochete.

As mentioned above, the β-lactam derivatives and non-toxic salts thereof of the present invention are superior in that they have a broad antibacterial spectrum, and have several antibacterial activities that are superior to those of known compounds (
For example, see JP-A-56-161'394), it has superior activity.

It is particularly useful in that it has excellent antibacterial activity against positive bacteria and β-lactamase producing bacteria.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these examples.

Example 1 C! HOOH OHO0HO (1) (2) 2-formyl-2-(2-formylaminothiazole-
After suspending 2.425' of ethyl (4-yl) acetate in 50 d of dry methylene chloride, 1.21 ml of pyridine was added dropwise under water cooling and dissolved. Add triphenylphosphine 3 to this solution.
．． After processing 931, 3.81 f of iodine was gradually added, and the mixture was stirred for 15 minutes under water cooling and then for 20 hours at room temperature.

After the reaction, 1 me of methanol was added to the reaction solution, then 150 ml of ethyl acetate was added, then water and 5% thiosulfuric acid were added.
After washing with IJum aqueous solution, water, and saturated saline in this order, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, it was purified by silica gel chromatography to obtain colorless crystals of 0.85 F of ethyl 2-iodomethylene-2-(2-formylaminothiazol-4-yl) acetate [isomer B]. Ta.

2-iodomethylene-2-(2-formylaminothiazol-4-yl)ethyl acetate [isomer B] Engineering R (KBr): 1700.1685.1560c
m-”NMRδ(d,-DMSO)2 1.25(
t, J-7Hz, 3H).

4.18 (q, J-7Hz, 2H), 7. +7(s, I
H).

a: z (s, IH), a52 (s, IH), 12.3 (
b's, IH) 2=formyl-2-(2-formylaminothiazole-
4-yl)ethyl acetate5. Of Dry Noterene Chloride 75
After suspending m1VC, potassium carbonate 5431 was added under water cooling and stirred for 1 hour.

Then 0-nitrobenzenesulfonyl chloride5.
25 d of dry methylene chloride in which 32 F was dissolved was added dropwise,
The mixture was stirred at room temperature for 18 hours.

After the reaction, methylene chloride was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine, and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, it was purified by silica gel chromatography, recrystallized from benzene, and 2-(
o-nitrobenzenesulfonyloxymethylene)-2-
2-(o-nitrobenzenesulfonyloxymethylene)
-2-(2-formylaminothiazol-4-yl)ethyl acetate R (KBr): 1710,1690,1630,1
535. -INMRδ((16-DMSO): tz
s(t, J-7Hz, 3H).

4.19 (q, J-7H2, 2H), 7.29 (s, I
H).

7.74 (s, IH), 7.9-8.4 (m, 4H),
a48 (s, IH), 12.5 (bs, 111)
(3)--→ (2) 2-(o-nitrobenzenesulfonyloxymethylene)
-2-(2-formylaminothiazole was dissolved in 50 tnl, triethylbenzylammonium iodide 6,38 F and 0.25 rnl of boron trifluoride/ethyl ether complex salt were added thereto, and the mixture was stirred for 15 hours.

The solvent was distilled off under reduced pressure, 150 d of ethyl acetate was added, and the mixture was washed successively with water, an aqueous solution of sodium 5-titeosulfate, water, and then saturated brine, and then dried over magnesium sulfate. Under reduced pressure
The solvent was distilled off and ethyl 2-iodomethylene-2-(2-formylaminothiazol-4-yl)acetate [isomer B
] 2.692 colorless crystals were obtained.

(HO 2-Iodomethylene-2-(2-formylaminothiazol-4-yl)ethyl acetate [isomer B] was dissolved in 20 ml of dry ethyl acetate, and heated under a high-pressure mercury lamp (4'00 W).
) The mixture was stirred for 5.5 hours under direct irradiation (the ratio of isomers A and B was determined to be 1:2 from the integral ratio of NMR protons).

After concentrating the reaction solution, it was purified by column chromatography to obtain colorless crystals 520i of ethyl 2-iodomethylene-2-(2-formylaminothiazol-4-yl)acetate [isomer A]. At the same time, isomer B, which is a raw material,
1.022 was obtained.

2-iodomethylene-2-(2-formylaminothiazol-4-yl)ethyl acetate [isomer A] ■R (KBr): 1700.1690.1530c
r++-'NMRδ (ds-DMSO): 1.33
(t, , T-7H2, 5H).

4.33 (q, J-7H2, 2H), 7.24 (s, I
H).

Z51 (s, IH), a49 (s, IH), 12.3 (
be, 'LH) CH engineering (5) Under water cooling, ethyl 2-iodomethylene-2-(2-formylaminothiazol-4-yl) acetate [isomer A] 45
Add 7W to an aqueous solution of tri-potassium hydroxide and heat to 85% at the same temperature.
I stirred for hours.

After the reaction, the pH was adjusted to 7.0 with 1 oelv acid aqueous solution under water cooling.
After washing with ethyl acetate and then distilling off the organic G medium in the aqueous layer under reduced pressure, the concentration was reduced to 10%! The pH was adjusted to 2.3 with an aqueous solution of phosphoric acid. The precipitated crystals were collected, washed with water, and dried to obtain 387 cm of colorless crystals of 2-iodomethylene-2-(2-polmylaminothiazol-4-yl)acetic acid [isomer A].

2-iodomethylene-2-(2-polmylaminothiazol-4-yl)acetic acid IR (KBr): 1700.1670.164.0
．． 1555 100'NMRδ (d6-'DMSO):
727 (s, in), 7.37 (s.

1H), as0(s, IH), 12.3(M, IH)0
020 HP b2 (6) (7) 2-iodomethylene-2-(2-polmylaminothiazol-4-yl)n″ “Eye [isomer A] 340■ and 7
-Amino-6-(1,3,4-thiadiazol-2-yl)theomenal-3-cephemu-4-carboxylic acid benzhydryl ester 476
(F) After suspending in 5 ml, 255 μl of dicyclohequinlecarbodiimide was added and stirred at room temperature for 2 hours.

After filtering the reaction solution and concentrating the p solution, it was purified by silica gel chromatography, and 7-(:2-iodomethylene-
2-(2-formylaminothiazol-4-yl)acetamide 3-3- (1°6.4-thiadiazol-2
650 pale yellow amorphous crystals of benzhydryl)thiomethyl-5-cephem-4-carboxylic acid ester were obtained.

7-[2-iodomethylene-2-(2-formylaminothiazol-4-yl)acetamide] -3-(1,
3,4-thiadiazol-2-yl)thiomethyl-6-
Cephem-4-carboxylic acid benzhydryl ester R (KBr): 1775,1770,1665cr
n”NMRδ (a6-DMso): 3.7 6
(be, 2H), 4.24 (cl, J-14Hz,
IH), 4.53 (d, , r-14H2, IH)
, 5.28 ((1, J-5H2, IH), 5.93 (d
d, J-5,8Hz), 493(8,IH).

7.09 (a, IH), 7.33 (n+, 11H), a
s.

(B, IH), 9.46 (III, IH), 9.58 (
cl, J-8Hz, IH), 12.3 (be, 1H) (
8) 7-[2-iodomethylene-2-(2-formylaminothiazol-4-yl)acetamide] -3-(t
3.4-thiadiazol-2-yl)thiomethyl-3-
Cephem-4-carboxylic acid benzhydryl ester 56
0q was suspended in dry methanol, 0.24 g of phosphorus oxychloride was added dropwise under water cooling, and 11 i was added at room temperature. I fought for a while.

30 ml of ethyl acetate and 10 rnl of a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the layers, and the aqueous layer was extracted again with 10 rnl of ethyl acetate. Combine the ethyl acetate layers,
After washing with water and saturated saline, it was dried over magnesium sulfate.

After distilling off the solvent under reduced pressure, it was subjected to silica gel chromatography to obtain 7-[2-iodomethylene-2-(
2-aminothiazol-4-yl)acetamide]-3
380 square meters of pale yellow amorphous crystals of -(1,3,4-thiadiazol-2-yl)thiomethyl-6-cephem-4-carboxylic acid benzhydryl ester were obtained.

7-[2-iodomethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1,44-thiadiazol-2-yl)thiomethyl-5-cephem-4
-Carboxylic acid benzhydryl ester R (KBr): 1770, 1715, 1660, 1
610°1520p-l NMRδ((1,-DMSO): 5.75(t+8
．． 2H), 4.23(a, J-14Hz, IH), t
sz(a, J-14HE, 11), 5.26((1, J
-5H2, IH), 5.88 (d4. J-5,8Hz
, IH), &47(s, IH).

6.95 (B, IH), 7.11 (s, IH), 7.4
0 (m.

12H), 9.48 (s, IH), 9.5! +(d, J
=8H2,IH) OH engineering (9) 7-[2-iodomethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1,3,4-thiadiazol-2-ylcothiomethyl-3- Cephem
310Tq of 4-carboxylic acid benzhydryl ester was fermented and dissolved in dry methylene chloride a6- and anisole 0.3-, and after dropping 6 ml of trifluoroacetic acid Q under water cooling,
The mixture was stirred at the same temperature for 1 hour.

After the reaction, ethyl acetate 57! was added, and the pH was adjusted to pH with saturated aqueous sodium bicarbonate under ice cooling. After separation, the aqueous layer was adjusted to pH 6.5 with 1N hydrochloric acid and treated with activated carbon. Solution F was adjusted to pH 2.7 with 1N hydrochloric acid under water cooling and stirred for 1 hour. The precipitated crystals were collected, washed with water, and dried to give 7-[2-iodomethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1,3,4-thiadiazol-2-yl)thiomethyl. 136 kg of -6-cephem-4-carboxylic acid were obtained.

7-[2-iodomethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-
4-Carboxylic acid XR (KBr): 1765.165
5.1630.1525cmz-”NMRδ(a6-D
IJso) + 3.61 (a, :r= 17H2
, IH).

6.79 (d, J-17Hz, IH), 4.29 (d,
, T-13H2, IH), t62(a, J-13H2,
IH).

5.21 (a, J-5H2, 1H), 5.80 (dd,
J-5,8Hg, IH), 6.42 (t3.IH), 7
．． 08(s.

IH), 9.53 (d, J-8Hz, 1H), 9
．． 57 (s.

IH) Example 2 (11α■ α2-chloromethylene-2-(2-aminothiazole-4
2.04 f of ethyl acetate was suspended in 20 of ethyl acetate, cooled to -30°C, and Vilsmeier's reagent [5062 f of dimethylformamide (DMF) was added to 1.46 f of dimethylformamide (DMF) under cooling with water. Afterwards, heat at 50°C for 50 minutes,
Then, 30 - of THF was added to prepare] All of the mixture was lowered and stirred at the same temperature for 5 minutes, and then the temperature was raised to -5°C for fermentation.

2.16 y of 6-amitubenicilanic acid was suspended in 50 ml of water, 2.12 y of sodium bicarbonate was added thereto, and then THF 5 o- was added.

The above liquid n was added dropwise to this solution under water cooling while adjusting the pH to 7.5 to a5, and stirred at the same temperature for 1 hour.

Ether acetate and THF were distilled off under reduced pressure to adjust the pH to 7,
After washing with ethyl acetate, the pH was adjusted to 5 to obtain precipitated crystals. After dissolving this crystal in a sodium hydrogen carbonate hydroxide solution, it was purified using Diaion HP-20 (manufactured by Mitsubishi Chemical Industries, Ltd.).
[2-chloromethylene-2-(2-aminothiazole-
Yellow-brown amorphous crystals a411 of sodium 4-yl]acetamido]-penicillanate were obtained.

Sodium 6-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-beninlanate JR (KBr): 1760. 1640 (7B-”
NMRδ(a,-DMso): 1.51(8,5H
), 1.56(8°3H), &97(s, 11(),
5.53 (be, 2H).

6.45 (21H), 6.82 (s, IB), 7.14
(be, 2H), 9.19 (d2.T-8H2, IH)
Example 3 (2-formylaminothiazol-4-yl)glyoxylic acid benzhydryl ester 1.83y to phenylethoxycarponyl bromomethelenephosphorane 520
2 was dissolved in 50 d of dry benzene and boiled for 5 hours.

After concentrating the reaction solution, it was purified by silica gel chromatography and purified by 2-ethoxycarbonylbromomethylene-2-
Colorless crystals of (2-formylaminothiazol-4-yl)Dk acid benzhydryl ester 1,50 f [isomer A], 0.6Of (isomer B) were obtained.

2-Ethoxycarbonyl bromomethylene-2-(2-formylamitunaazol-4-yl)acetic acid benzhydryl ester [isomer A] NMRδ (CDCl3): 1.15 (t, J-7
H2, 3H).

4.20 (q, J-71 (z, 2H), 6.78
(S, IH), 7.05 (s, IH), 7.30 (s
, 10H).

a45 (ii, IH), 10.73 (8, IH) [isomer B] NMR δ (c: oaz3): t17 (t, , T-
7J (Z, 3H).

4.03 (q, J-7H2, 2H), 6.94 (e, I
H), 720 (s, 10H), 7.44 (s, IH).

a47 (s, IH), 11.18 (6, IH) (t) 2-ethoxycarbonyl bromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid benzhydryl ester [isomer A 30.42 In methylene chloride 0.8 ml and anisole 0.4rn1. 0.8-trifluoroacetic acid was then added under water-cooling and stirring. After 20 minutes, methylene chloride was distilled off under reduced pressure, ether was added, and the pH was adjusted to 7 with saturated sodium bicarbonate water @taka.
Washed with ether. Thereafter, ethyl acetate was added to the aqueous layer, the pH was adjusted to 2.5 with 1N hydrochloric acid, the pH was adjusted to 2.5 with 1N hydrochloric acid, the extract was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over magnesium sulfate. Ethoxycarbonylbromomethinone-2-(2-formylaminothiazol-4-yl) vinegar fJ'i/0.28? was obtained.

2-ethoxycarbonylbromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid NMRδ (CDCl2): 1.20 (t, J-7
H2, 3H).

4.23 (q, J-7Hz, 2H), 7.14 (s, I
H).

a58(s, IH), 11.65(8,2H)0Q 2-ethoxycarbonylbromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid 270~ and 7-amino-5-(1,5 ,4-thiadiazole-2-
382 Tng of thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester was dried in TH'F 8-
Synchhexylcarbodiimide 246
(2) was added and stirred at room temperature for 55 hours. After filtering the reaction solution and concentrating the filtrate, it was purified by silica gel chromatography to obtain 7-(2-ethoxycarbonylbromomethylene-2-(2-formylaminothiazol-4-yl)).
370 tons of yellow amorphous crystals of acetamido]-3-(1,!l, 4-thiadiazol-2-yl)thiomethyl-5-cephem-4-carboxylic acid benzhydryl ester
ng was obtained.

7-(2-ethoxycarbonylbromomethylene-2-(
2-formylaminothiazol-4-yl)acetamide 3-3-(t3.4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester NMRδ (ODO63): 1.10
(t, J-7H2,3H).

3.73 (bs, 2H), 4.14 (q, J-7I (Z
, 2H).

4.45 (qAB, J-14H2, 2H), 5.1
7 (d, J-5Hz, IH), 6.12 (dd
, J-5,9,H2,IH), 6.72(s,IH)
, 6.96 (Japanese, IH), Z30 (m, 10H),
a22 (s, IH), a40 (d, J-9H2, IH)
, a90(s, IH), 10.72(be.

IH) To 5 wtt of dry methanol and 3 m of dry THP, add phosphorus oxychloride 0,4- while stirring with water cooling, and add 7-[2-ethoxycarbonyl bromomethylene-2-
(2-formylaminothiazol-4-yl)acetamide] -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (0.91%) was added, and at room temperature I stirred it for an hour. Ethyl acetate was added to the reaction solution, the mixture was adjusted to p)17 with sodium bicarbonate hydroxide solution, the ethyl acetate layer was separated, and the aqueous layer was extracted again with ethyl acetate. The extracts were combined, washed with water, and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the 7-
(2-ethoxycarbonylbromomethylene-2-(2-
aminothiazol-4-yl)acetamide]-3-(
1,5,4-thiadiazol-2-yl)thiomethyl-
630 yellow amorphous crystals of 3-cephem-4-carboxylic acid benzhydryl ester were obtained.

7-[2-ethoxycarbonylbromomethylenelene-2
-(2-aminothiazol-4-yl)acetamide]
-3-(1,3,4-thiadiazole-2-(l)thiomethyl-6-cephem-4-carboxylic acid benzhydryl ester NMRδ(anat3): tz(t, J-7H2
, 3H).

563 (bs, 2H), 4.15 (q,, T-7H2,
2H).

4.45 (qAB, J-14H2, 2H), 5.0
0 (d, J-5H2, IH), 5.47 ('be, 2
H), 5.95 (dcl.

'Sai J-5,8Hz, &50(s, IH), 6.90(
8゜jH)', 7.30 (m, 10H), a08 (d,
J-8H2, IH), &85(s, IH) αε9 7-C2-xtrrdicarbonylbromomethylene-2-
(2-aminothiazol-4-yl)acetamide 3-
5-(1,5,4-Thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester α6f was added to 1.2 ml of dry methylene chloride and 0.6-ml of anisole, then water-cooled and stirred. , trifluoroacetic acid 1.2- were added thereto, and the mixture was stirred at the same temperature for 20 minutes.

Ethyl acetate was added to the reaction solution, the pH was adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution, the tar-like substance was separated from F, and the mixture was separated to obtain an aqueous layer. Ethyl acetate in the aqueous layer was distilled off under reduced pressure, the pH was adjusted to 6.5 with 1N hydrochloric acid, the precipitate was separated, and the pH was adjusted to
It was set as 2.7.

The precipitated crystals were collected, washed with water, and dried to give 7-[2-methoxycarbonylbromomethylene-2-(2-aminothiazol-4-yl]acetamido]-3-(1,S, 4-thiadiazol-2-yl). ) Thiomethyl-3-cephem-
Colorless crystals of 4-carboxylic acid 0.21 were obtained.

7-(2-methoxycarbonylbromomethylene-2-(
2-aminothiazol-4-yl)acetamide] -
3-(1,!l, 4-thiadiazol-2-yl)thiomethyl-6-cephem-4-carboxylic acid NMR δ((16-DMSO): 1.22(t,
J = 7H2, 5H).

3.74 (qAB, J-18Hz, 211),
4.27 (q, J= 7 H2,2H), 4.49
(qAB, J = 13Hz, 2H).

5.23 (a, J-5Hz, IH), s, al (aa,
y-5,8H2,IH), 6.58(s, IH), 7.
10 (b.s.

2H), 7.37 (be, IH), 9.62 (s, IH
).

9.95 (eL, J-8Hz, IH) Example 4 (Uniform (2-formylaminothiazol-4-yl)glyoxylic acid benzhydryl ester 1.83F)! J Phenylmethoxycarbonyl bromomemethine phosphorane &1
0F and 50°C of dry benzene and refluxed for 9 hours. After concentrating the reaction solution, it was purified by silica gel chromatography, and 2-methoxycarbonyl bromomethylene-2
-(2-formylaminothiazole-4-i/')
Colorless crystals of benzhydryl acetate t 36 y
[:isomer A] and α581 [isomer B] were obtained.

2-Methoxycarbonyl bromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid benzhydryl ester [isomer A] NMR δ (aDats): 5.75 (s, 3H),
6.70 (s.

IH), 7.05 (Japanese, IH), 7.30 (s, 10H)
), a37 (s, IH), 1a33 (be, 1 ■) [isomer B] NMR δ (ODOt3): 552 (s, 5H),
6.95 (s.

IH), 7.22 (s, IH), 7.55 (s, IH)
.

a41 (s, IH), 10.45 (bs, IH) 42-methoxycarbonyl bromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid benzhydryl ester [isomer A] Drying 1.31 2.6 d of methylene chloride and 1.3 d of anisole were added, and then 2.6 d of trifluoroacetic acid was added while stirring with water cooling. After 10 minutes, methylene chloride was distilled off under reduced pressure, ether was added, the pH was adjusted to 7 with saturated sodium bicarbonate, and the mixture was washed with ether. Thereafter, ethyl acetate was added to the aqueous layer, the pH was adjusted to 2.5 with 10% phosphoric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 2-methoxycarbonyl bromomethylene-2-(
2-formylaminothiazol-4-yl)acetic acid a, s
Obtained qy.

2-Methoxycarbonyl bromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid NMR δ (d6-DMSO): 3.83 (s, 3H
), 7.27 (e.

IH), α47(s, 1H) Qυ 2-methoxycarbonylbromomethylene-2-(2-formylaminothiazol-4-yl)acetic acid 0.7f and 7-amino-3-(1,3,4-thiadiazole- 2-
yl)thiomethyl-5-cephem-4-carboxylic acid benzhydryl ester α99v was dried in THF 22 tn.
dicyclohexylcarbodiimide 45
3 pieces were added and stirred at room temperature for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel chromatography to give 7-[2-methquinecarbonylbromomethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3- Yellow amorphous crystals of (1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 1.32
I got t.

7-[2-methoxycarbonylbromomethylene-2-(
2-formylaminothiazol-4-yl)acetamide] -3-(1,3,4-thiadiazol-2-yl)thiomethyl-6-cephem-4-carboxylic acid benzhydryl ester NMRδ (C!DC63): 3. 6
0 (Ifl, 3H), A66 (be.

2H), 4.36((LAB, J = 14Hz, 2
H), 5.16(a, J, = 5I(Z, IH),
6.1o (aa, y-s, sH2, IH), 6.7
5 (8, IH), 6.96 (8, IH).

7.2-7.4 (10H), α23 (s, IH), 8.
42 (d, J-BH2, IH), a91 (s, IH)
.

1 α76 (be, 1H)) To 3 ml of dry methanol and dry THF 3-, add 0.53 ml of phosphorus oxychloride while stirring on ice, and add 7-[2-methoxycarbonylbromo methylene-2- to this vinegar solution.
(2-formylaminothiazol-4-yl)acetamide] -3-(1,3゜4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1.2f) was added, and at room temperature I stirred it for an hour. Add ethyl acetate to the reaction solution, and dilute with 10% sodium hydroxide aqueous solution and saturated sodium hydrogen carbonate aqueous solution.
H7 and extracted with ethyl acetate. The extracts were combined, washed with water, and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the 7-
[2-methoxycarbonyl bromomethylene-2-(2-
aminothiazol-4-yl)acetamide] -3-
Yellow amorphous crystals 870 of (1,5,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester were obtained.

7-[2-methoxycarbonylbromomethylene-2-(
2-aminothiazol-4-yl)acetamide] −
3-(1,5,4-thiadiazol-2-yl)thiomethyl-6-cephem-4-carboxylic acid benzhydryl ester NMR δ (ODO63): 3.6-57 (bs,
5H), 4.33(qAE, J-14Hz, 2H
), 5.00 ((1, J-5H2, IH), 5.45
(bs, 2H), 5.90 (ad.

J-5, 8Hz, IH), 6.51 (S, IH), 6
．． 90 (1g, 1H), 72-74 (10H), al
O(d.

J-8Hz, 1H), aa7(s, IH)7-[2-
Methoxycarbonyl bromomethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1,3
,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 850
was added to 1.7 L of dry methylene chloride and 8 m of anisole, then water-cooled and stirred with 1.7 L of trifluoroacetic acid.
- was added and stirred at the same temperature for 40 minutes. Ethyl acetate was added to the reaction solution, and the pH was adjusted to 7.5 with a 10% aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution, and the tar-like substance was removed from the p side and separated to obtain an aqueous layer. Ethyl acetate in the aqueous layer was distilled off under reduced pressure, and the pH was adjusted to &5 with 1N hydrochloric acid, and the precipitate was adjusted to the F side edge, pH 2.7. The precipitated crystals were collected in a furnace, washed with water, and dried to give 7-[2-methoxycarbonylbromomethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1°6.4-thiadiazole-2-
173 capes of colorless crystals of yl)thiomethyl-5-cephem-4-carboxylic acid were obtained.

7-[2-methoxycarbonylbromomethylene-2-(
2-aminothiazol-4-yl)acetamide] -
5-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid NMRδ (d6-DMSO): 3.72 (qAB,
J-18H2, 2H),! 1b7B (Japanese, 3H), 4.
47 (qAB, J-14H2,2H), 5.2!
(a, J-5Hz, IH), 5.80 (dcl,
J=5.8H2, IH), 6.56(s, IH)
.

9.60 (s, IH), 9.92 ((1, J-8Hz,
IH) Example 5 (c) (c) 535 ml of HO 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid was dissolved in 3 m of dry THF, and dicyclohexylcarbodiimide 28 ml was dissolved under water cooling.
To 4! pf was added and stirred for 2 hours.

565 ml of 7-amino-3-[tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid was dissolved in 8-ml of water, 3 ml of acetone, and a saturated aqueous sodium carbonate solution, The pH was set to 6.

The above solution was added to this fattening solution under water cooling, and after 45 minutes, the reaction solution was filtered, and the filtrate was washed with ethyl acetate and then with benzene.
The pH was adjusted to 6 with 1N hydrochloric acid, the precipitate was separated, and the pH was further adjusted to 3.
And so. The precipitate was collected, washed with water, dried, and 7-[2-chloromethylene-2-(2-formylaminothiazole-4
-yl)acetamide]-5-[tetracylo(t s
-b) 540 μ of light brown crystals of pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carvone Acid NMRδ (d6-DMSO): 3.72 (qAB
, J-18Hz, 2H), 4.40(qA]lb I
-13Hz, 2H), 5.19 (d.

J-5H2, IH), 5.83 (clcl, J-5
,8Hz.

IH), 7.04 (s, IH), 7.06 (s, IH)
.

7.76 (d, J-10Hz, IH), a50 (s, I
H).

ass+(a, J-10Rz, IH), 9s6(
a, J-8Hz, IH), 12.46 (be, IH)
(a) To 56 ml of dry methanol and 37ml of dry THF, add 1,86ml of phosphorus oxychloride while stirring on ice, and add 7-[2-chloromethylene-2-(2-formylaminothiazole-4- yl)acetamido]-3-Ctetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid (5.79 f) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution, the pH was adjusted to 7 with a saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 2 after washing with ethyl acetate and then benzene. The precipitate was collected in F, washed with water, dried, and converted into 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[tetracylo(ts-b)pyridazin-6-yl]. Thiomethyl-3-cephem-4-
Colorless crystals of carboxylic acid t772 were obtained.

After dissolving this in a saturated aqueous sodium hydrogen carbonate solution, HP
-20 column for purification to obtain the sodium salt.

7-[2-chloromethylene-2-(2'-aminothiazol-4-yl)acetamide]-5-[tetracylo(
1,5-b) pyridazin-6-yl]thiomethyl-3
-cephem-4-carbo NMRδ (d6-DMSO)
: 5.72 (qAB, J-18H2, 2H), 4.
40 ((LAB, J = I SH2, 2H), 5.18
(d, J-5Hz, IH), 5.79 (ad, J-5,
8H2, IH), 6.39(e, II(), 6.84(
El, IH), 7.16 (j+day, 2H), 7.75 (
d,, J-10H2, IH), a, 5a (d, J=10
Hz, IH).

9.58 (J J-8Hz, IH) Example 6 (e) 6-mercabuto 8-methyl-tetracylo(1,5-b
) Pyridazine 1.15 F and sodium bicarbonate 1
．． 169 to 10 dipotassium hydrogen typhosphate buffer (pHA
5) Suspended in 69- and heated to dissolve at 50°C. Next, 1.87 t of 7-amituse7allosboranic acid was added little by little, followed by stirring at 80°C for 2.5 hours. After stirring the reaction solution for 30 minutes under water cooling, the precipitated crystals were collected in a furnace, washed with water,
Dried, 7-amino-3-[8-methyl-tetracylo(
1,s-b)pyridazin-6-yl]thiomethyl-
Light brown crystals of 3-cephem-4-carboxylic acid 2.08
I got f.

7-Amino-3-(8-methyl-tetracylo(: 1.
5- b ]pyridazin-6-yl)thiomethyl-3-
Cephem-4-carboxylic acid NMRδ (D20-1-0F3002D): 2.7
5 (s, 3H)t3.85(qAB, J-187(
Z, 2H), 4.24 (d.

J-15Hg, IH), 5.05(d, J-15Hz,
1H), 5.23 (g, 2H), 7.30 (S, IH
) ■ 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid 2.79 f dried THF 15
．． 7 d, dicyclohexylcarbodiimide (1.49 F) was added under water cooling, and the mixture was stirred for 2.5 hours.

7-amino-3-[8-methyl-tetracylo(1,s
-b) 1.989 of pyridazin-6-ylcothiomethyl-6-setuemu-4-carboxylic acid was suspended in 34 of water,
Under water cooling, the pH was adjusted to 10 with a 10% sodium hydroxide aqueous solution, then the pH was adjusted to 5 with 1N hydrochloric acid, and then acetone was added.
5- was added.

The above bath solution was added to this solution and stirred for 1.5 hours. Insoluble matter was removed from the p side, washed with ethyl acetate, then the organic solvent in the aqueous layer was distilled off under reduced pressure, and the pH was adjusted to 3 with 1N hydrochloric acid under water cooling.
And so. The precipitated crystals were washed several times with water and dried to give 7-[2-chloromethylene-2-(2-formylaminothiazole-
Light brown crystals of 4-yl]acetamido]-3-(8-methyl-tetracylo(1,s-b)pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid3.
069 was obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[8-methyl-tetracylo(1,s -b)pyridazin-6-yl]thiomethyl-6-cephem -4-carboxylic acid NMR δ (+1.-DM80): 2.64 (θ, 3
H), 571 (qAB, J-18H2, 2H), 4.
17 (d, J" t 4H2, IH), 4.60 (d
, J-14Hz, IH).

5.19 (d, J-5Hz, 1H), 5.82 (dd
, :J-5,8H2,IH), 7.04(s,IH),
706 (s.

IH), 7.60 (s, IH), a50 (s, IH).

p, 56 (a, y-sHz, 1u), 12.4 (bs,
IH)0]) Methanol 27.4 me, THF 27.4 ml
and 2.74 m of water, 5.0 - of concentrated sulfuric acid was added dropwise, and to this solution was added 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[
8-Methyl-tetracylo(t5-b)pyridazine-6
-yl]thiomethyl-3-acid cefem-4-carvone (72.95 f) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, adjusted to pH 7.2 with 28% ammonia water, and washed with ethyl acetate. Ethyl acetate in the aqueous layer was distilled off under reduced pressure, the pH was adjusted to 5.5 with 1N hydrochloric acid, and the pH was adjusted to X1 after removing insoluble matter. The precipitated crystals were washed several times with water and dried to give 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(8-methyl-tetracylo(1,5-b)
)pyridazin-6-yl)thiomethyl-6-cephem-
Light brown crystals z071 of 4-carboxylic acid were obtained.

After dissolving this in a saturated sodium bicarbonate water bath solution, HP
-20 column for purification to obtain the sodium salt.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-methyl-tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem- 4-carboxylic acid NMR δ (d6-DMSO): 2.64 (e, 3
H), 3.70 (qAB, J-18H2, 2H), 4
．． 16 (d, J = 15Hz, IH), 4.60 (
d, J-13H2, IH).

5.17 (d, J-5Hz, IH), 5.79 (da,
Jx5.8H2, IH), &3B(s, IH), &83
(s.

IH), 7.16 (be, 2H), 9.59 ((1, J
-8H2゜IH) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(8-methyl-tetrazoo (1,s -b ) biritacin-6-yl]
Sodium thiomethyl-3-cephem-4-carboxylate NMRδ (ad-DMso): 2.63 (E+,
3H), 3.49(qAB, J = 17H,
Z, 2H), 4-” (qAB, J-12
Hz, 2H), 5.05 (d, J'-5H2, IH).

5.60 (ad,, J-5,8Hz, iH), 6.39
(s.

IH), 6.82 (s, IH), 7.1s (be, 2H
).

7.62 (S, IH), 9.50 (d, :f-8H2,
IH) Example 7 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1
H-tetrazol-5-yl)thiomethyl-5-cephem-4-carboxylic acid sodium salt (asp) was dissolved in water (2
ml) and left at room temperature for one week. The reaction solution was filtered and 7-[2-formyl-2-(2
-aminothiazol-4-yl)acetamide,]-3
-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.

NMRδ (d6-DMSO): 568 (qAB,
J-1f3Hz, 2H), X96(e, 5H),
4.38 (qAB, J-10H2, 2H), 5.12 (
(1, J-4H2, 1H), 5.82 (ad, , T-
2Hz, J-8Hz, 11), 6.76(e.

IH), 7.60 (bs, 2H), 786 (s, IH)
.

9.90 (d, J = 8 Hz, 1H) Example 8 50% sodium hydride (0,2' 8 f, 11.7
m mot) t After washing with n-hexano, dehydrated ether (15-) is added. On the other hand, ethyl 2-furylacetate (
1,2F, 7.8mmot) and ethyl formate (α86f
, 11.7. mmot) was dissolved in dehydrated ether (157) and added dropwise to the above ether-sodium hydride suspension at room temperature. After the dropwise addition, the mixture was stirred at 30° C. for 1 hour and at room temperature for 16 hours, and then the reaction mixture was adjusted to pH 6 with an aqueous ammonium chloride solution. Extracted twice with ether (150d) and twice with ethyl acetate (100++/liter), and the organic layer was washed with brine and dried over anhydrous sodium sulfate.

The solvent was evaporated under reduced pressure to obtain ethyl 2-formyl-2-(2-furyl)acetate (1,41F, 98%) as a brown oil.

NMRδ(aDat3): tos(t,:r-yHw
, 3H).

4.33 ((1, J-7Hz, 2H), 6.30(m
, 2H).

7.23 (m, IH), 7.70 (bs, IH) Mass spectrometry nue (%): 182 (23), 1! +6 (10
0).

108(26) Triphenylphosphite (2,5fj!, 7.4mm
ot) in methylene chloride (18 m), and while cooling with water, chlorine gas is passed through the solution until the solution turns yellow. Then, triphenyl phosphite is added until the solution becomes colorless. Ethyl 2-formyl-2-(2-furyl)acetate (0.9F, 4.9 mmot) was then dissolved in methylene chloride (2
2d) was added dropwise and allowed to stand at room temperature for 1.25 hours.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (250+
1d). The organic layer was washed three times with aqueous sodium bicarbonate solution and twice with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a black clear product. Purified by column chromatography to obtain 2-chloromethylene-
2-(2-furyl) x thyl acetate (a, s2t, s2%)
(isomer mixture) was obtained as a yellow oil.

NMRδ(aDat,): t4o(t, , r-7
Hz, 3H).

4.46 ((1, J-7Hz, 2H), 6.53-7.
59 (m, 3H) Mass spectrometry Ve (%): 202 (50), 200 (8
8).

165 (77) Sodium hydroxide (0,57?, 14 mmot) 1:(
Dissolved in ethyl 2-chloromethylene-2-(2-furyl)acetate (0.71f).

3, s 4 m mot ) was added dropwise to a suspension of water (6d) at 0 to 2°C for 30 minutes. After dropping, leave at room temperature for 25 minutes.
After stirring for an hour, the reaction mixture was extracted with ether. The aqueous layer was adjusted to pH 2 with 2N hydrochloric acid at 0°C, and ethyl acetate (
Extracted twice at 100+d). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was reduced and distilled off under pressure, and 2-chloromethylene-2-(2-furyl)acetic acid (
0,52,83%) (mixture of isomers)'lc-obtained as a reddish-brown oil.

NMRδ (ODOt3): 6.4-6.5 (m,
IH), 6.67(d, IH), 713.7.5
9(twos, 11().

7.46-7.48 (m, IH), 10.59 (bs,
IH) Mass spectrometry m7e (%): 174 (34), 1
72 (100).

130 (59), 127 (20) Under an argon atmosphere, potassium (0.47 W, 12 mmot) was added to anhydrous t-butanol (5 rrt), and 2.5
A potassium t-butoxide solution was prepared by heating under reflux for an hour. Add chloromethyltriphenylphosphonium iodide (2,19, 5 mmot) to this acid solution under water cooling.
was added little by little and stirred at room temperature for 1.5 hours. Next, t-furylglyoxylic acid was added to this reaction mixture.
The mixture was dissolved in butanol (5-) and added dropwise, followed by stirring at room temperature for 17 hours. Ether acetate and water were added to the reaction mixture, the pH was adjusted to 6 with 50% acetic acid aqueous solution, and ethyl acetate (i00
Extracted with rn/ri. The aqueous layer was adjusted to pH 2 with 2N hydrochloric acid, extracted twice with ethyl acetate (100 tnt), and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 2-
Chloromethylene-2-(2-furyl)acetic acid (o, 18, 42%) (isomer mixture) was obtained.

Hat 2-chloromethylene-2,=(2-7!J)acetic acid (0
, 6t, 148mmot) in dry methylene chloride (20#
After dissolving I7 in a mixed solvent of 171 ml of dry ethyl acetate (20+ml), 7-amino-3-(1-methyl-1H-
Tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid benzhydryl ester (1,72f,
3.48 mmot), then Do(! (Q, 72
t, 148 mmot) was added. Dry THF (15d) was further added to the reaction mixture and stirred at room temperature for 195 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (160d) and filtered. The ν solution was concentrated under reduced pressure and purified by column chromatography to obtain 7-(2-chloromethylene-2-furyl)acetamido-6-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3.
-cephem-4-carboxylic acid benzhydryl ester (
A mixture of isomers) (o, 7r, 511) was obtained as orange crystals.

NMRδ(a6-DMSO): N65(qAB,
I-BH2, 2H), N92 (g, 5H), 4.30 (
(IAB, :J-14H2, 2H), 5.06-5.
20 (m, IH), 5.56-5.84 (m, IH
), &1~777 (m, 15H).

9.48. 9.66 (twod, J-8Hz, 11
()Hat 7-(2-chloromethylene-2-furyl)acetamido-5-(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (0,67F, 1.03 mmot) was dissolved in anisole (2II! g), and trifluoroacetic acid (2,38 rnt) was added dropwise over 12 minutes under water cooling. After dripping,
After stirring at 0° C. for 2.5 hours, the reaction mixture was condensed under reduced pressure. Ether acetate (1Ω) was added to the residue, the pH was adjusted to 7.5 with an aqueous sodium bicarbonate solution, and the mixture was filtered through Celite. Solution F was extracted twice with ether (60 ml), and the aqueous layer was adjusted to pH 2.4 with 2N hydrochloric acid under water cooling and stirred for 1 hour. Crystals precipitate and are filtered,
7-(2-chloromethylene-2-furyl)acetamido-5-(1-mete-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid (0,29
F, 62%) (liquid chromatography) isomer ratio A
:B-3:2) was obtained as brown crystals.

NMRδ(d4-DMSO): 5.70(be,
21H), 3.92 (s, 3H), 4.30 (qAB
, J'-10H2,2H).

5.14 (m, IH), 5.74 (m, IH),
6.5-7.8 (m, 4H), 9.48.9.6
6 (twod, J-8Hz.

IH) Example 9 σHot OH8CjH20020HPh2 1 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-1
H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (385-
, 0.6 mmot) was dissolved in DMF (10@/ ) and α-mercaptoacetic acid benzhydryl ester (160
cape.

[16 m rnot ), triethylamine (70 m rnot ), triethylamine (70 m rnot
.

(17 mno/, ) was added and stirred at room temperature for 12 hours. Water and ethyl acetate were added, and the organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. After filtration, the Chiang medium was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7-(2-carboxymethylthiomethylene-2-(2-aminothiazol-4-yl)acetamide, 1l-3- (1-Methyl-1H-tetrazol-5-yl)thiomethyl-6-cephem-4-
Carboxylic acid bisbenzhydryl ester (155, 5
0%) and 7-[2-carboxymethylthiomethylene-2
-(2-aminothiazol-4-yl)acetamide]
-2-cephem-4-carboxylic acid bisbenzhydryl ester (220 mg, 43 units) was obtained.

7-[2-carboxymetheltheonoterene-2-(2-
aminothiazol-4-yl)acetamide]-3-(
1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid bisbenzhydryl ester NMRδ (ODC63): 145 (B, 2H
), 3.70 (s.

2H), A31 (s, 3H), 427 (bs, 2H).

4.97 (eL, J-4H2, IH), 5.91 (m,
IH).

6.80 (s, IH), 6.93 (e, IH), 7.0
1~7.42 (m, 20H) OH8C! H,0020HPh2 1 7-(2-carboxymethylthiomethylene-2-(2-
aminothiazol-4-yl)acetamide]-3-(
Dissolve 1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid bisbenzhydryl ester (150tIIg, 0.2mmot) in a mixed solvent of methylene chloride (5d) and anisole (1-). Then, trifluoroacetic acid (0.5 ml) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was made basic with an aqueous sodium bicarbonate solution, and then the aqueous layer was separated.

The aqueous layer was adjusted to pH 2 with 2N hydrochloric acid, the precipitated crystals were filtered,
7-[2-carboxymethylthiomethylene-2-(2-
aminothiazol-4-yl)acetamide]-5-(
1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (50■, 42%)
(isomer ratio A:B-3:2) was obtained as yellowish-white crystals.

.

NMRδ (+16-DMSO): 165 (qAB
, J-18H2゜2H), &75(e, 2H), 3.
96 (s, 5H).

4.35 (qAB, J-14Hz, 2H), 5.
14 ((1°J-5H2, IJ(), 5.82.5.
87 (twodd, J-4H2, J-4Hz, IH
), 6.54.6.68 (tw.

s, IH), 7.50.7.68 (twos, I
H), 9.49°9.65 (twod, J-8H2,
IH) Example 10 02H O→ 0'3 3◆ To acetonitrile '55me, add 4.02 of 2-ethelthio-5-mercaptothiadiazole and 6.119 of 7-amituse 7 allosboranic acid, and while stirring, prepare ethyl boron trifluoride. After dropping ether complex salt a51d, the mixture was stirred at 45° C. for 1 hour. After cooling, it was poured into 100 d of water, and aqueous ammonia was added to adjust the pH to 4.0. After distilling off the acetonitrile, the solution was further concentrated and left for 3 days. The precipitated crystals were washed several times with water and dried to give 7-amino-3-(2-ethelthio-1,he4-thiadiazol-5-yl)thiomethyl-
Brown crystals Z042 of 3-cephem-4-carboxylic acid were obtained.

0→ 7-amino-3-(2-ethelthio-1,!% 4-thiadiazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid 2. Of and N, N-bis(trimethylsilyl)acetamide 2.08f and methylene chloride 30
solution K dissolved in addition to m, 2-chloromethylene-2-
(2-formylaminothiazol-4-yl)acetic acid2.
58f was dissolved in THF 30-, 1.069 g of dicyclohexylcarbodiimide was added, and the solution was stirred at room temperature for 2 hours.The solution was then stirred at room temperature for 60 hours. After concentrating this solution to dryness, water was added and an aqueous sodium bicarbonate solution was added to adjust the pH to 75 and dissolve the solution. After removing insoluble matter, wash with ethyl acetate, add 1N hydrochloric acid and adjust to pH 4.0.
After the precipitate was separated, 1N hydrochloric acid was added to adjust the pH to 5.0.

The precipitate was collected, washed with water, and dried to obtain 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl).
Acetamide]-5-(2-ethelthio-1,44-thiadiazol-5-yl)thiomethyl-3-cephem-
0.621 of yellow amorphous crystals of 4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-5-(2-ethylthio-1,3,4-theacyazol-5-yl)thiomethyl-3-cephem-4 -Carboxylic acid NMR δ (c16-DME+): 1.57 (t,
J-711z, 3H).

5.28 (q, J-7Hz, 2H), 3.72 (bs,
2H).

4.20 (d, J-14Hz, IH), 4.58 (d,
J-14H2, IH), 5.22 (d, J-5H2, I
H).

5.85 (m, IH), 7.08 (bs, 2H), a5
2 (s, IH), 9.64 (d, J=8Hz, IH).

12.40 (be, IH) HO1 O7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-5-(2-ethylthio-1,!l, 4-thiadiazole -5-yl)thiomethyl-3-cephem-4-carboxylic acid 0.62
f to 6 ml of THF and 6 m7 of methanol! The mixture was dissolved in a mixed solvent of , and concentrated hydrochloric acid [118d] was added thereto under water-cooling and stirring, followed by stirring at room temperature for 18 hours. After distilling off the solvent, add 20ml of water, wash the precipitate with water, dry it,
-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(2-ethelthio-
1,3,4-thiadiazol-5-yl)thiomethyl-
Brown amorphous crystals o, 45r (decomposition point 220°C) of 3-cephem-4-carboxylic hydrochloride were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(2-ethelthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4- Carboxylic hydrochloride salt MRδ (d6-DMSO): 1.35 (t, J
-7Hz, 3H).

A26 (q, J==7Hz, 2H), A71 (bs, 2
H).

4.56 (m, 2H), 5.20 (d,, J-5Hz,
IH).

5.78 (m, IH), 6.42 (s, IH), 6.8
8 (s.

IH), 9.55 ((1,J-7H2,1)1) Example 11 HO6 Starting material 7-[2-chloromethyvy-2-(2-aminothiazol-4-yl)acetamide]-3 -(1-
Carbamoylmethyl-1,2゜3,4-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (M form A) was reacted according to the method of Example 6, purified using Diamond Ion HP20,
Chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-carbamoylmethyl-
1,2,5,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (isomer A) was obtained.

T, R (KEr): 1760.1600. i 5
50(y(-”NMRδ(d6-DMEIO): !
L45 (q71B, J = 16H2,2H),
4. ri2(qAB, 12H2,2E), 5.05(
m.

2H), 5.64 (dd, J-6H2, J-8H2, I
H).

6.42 (s, IH), A86 (s, IH), 7.17
(bs, 2H), 7.49 (bs, 1H), 9.50
(d.

J=8Hz, IH) Elemental analysis value 017H15C4Ng05S3Na-H2
Calculated value as O: 0.3414:H, 2,86;N,
2t08 analysis value: 0.31.92 :H, 2,68
;N, 19.05 Example 12 7-C2-winterloromethyene~2-(2-aminothiazol-4-yl)acetami)'']-3-(1
-Methoxycarponylmether-1,Otsu3.4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (A-form A) was reacted according to the method of Example 6, and the diamond ion ffff using HP20, 7-
(2-chloromethylene-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-methoxycarbonylmethyl-1,2,3,4-tetrazol-5-
(l)thiomethyl-6-cephem-4-carboxylic acid sodium salt (isomer A) was obtained.

Engineering R (KBr): 1750.1600.1540c
rn-'NMRδ (d6 DMSO): 150(q
AB, J-i 6Hz.

2H), F B (s, 3H), 4.36 (qAB, J-
13H2, 2H), 5.07((1, J-6H2, IH
).

5.45 (s, 2H), 5.65 (ad, J-6Hz,
J-8H2, IH), A44 (s, IH), 6.88
(s, IH), 7.17 (bs, 2H), 251 (d
, J-8Hz.

1n) Elemental analysis value 01BH160/! JllI O683N
Calculated value as a: 0.3454:H, 2,71:N
, 18.83 Analysis value: 0.52-49:H, 2,4
5:N, 16.77 Example 13 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-
Hydroxyethyl-1,2,3゜4-tetrazole-5
-yl)thiomethyl-6-cephem-4-carboxylic acid (
Isomer A) was reacted according to the method of Example 6, and purified using Diaion HP20 to give 7-(:2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]- 3-(1-hydroxyethyl-1,
2,364-tetrazol-5-yl]thiomethyl-3
-Cephem-4-carboxylic acid sodium salt (isomer A)
I got it.

Engineering R (KBr): 3450.1760.1605c
m”NMRδ(d4-DMSO): 3.78(t,
J-5Hz, 2H).

4.36(bs, 2H), s, os(a, J+=
7H2, IH).

5.61 (ad,, T-7H2, J-BHz, IH),
6.42 (S, IH), 6.85 (8, IH), z, 1
s (bs, 2H), 9.47 (d, J-811z
, IH) Elemental analysis value 017H460tNg05S3
Calculated value as Na: 0.35.57; H, 2,81
:N, 19.52 Analysis value: C, 30, 43; 1(,
A18;N, 12.69 Example 14 COxHCH20N 7-[:2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1
-cyanomethyl-1,2,3,4-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (isomer A) according to the method of Example 6, purified using Diamond Ion HP20, and purified with 2-aminothiazol-4-yl)acetamide]-3-(1-cyanomethyl-1°2, he4-
Tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid sodium salt (isomer A) was obtained.

NMRδ(a6-DMSO): 3.48 ((IA
B, J = 20 Hz, 2H), 4.36 (qAB
, J-14Hz, 2H), 5.04 (J-5
Hz, IH), 5.37 (s, 2H), 5.6
4 (ad, J-5H2,, T-8H2, IH), 6
．． 45 (e.

1H), &85 (e, IH), 7.14 (bs, 2H)
.

9.48 (d, J-8H2, IT () Elemental analysis value C17H130C17H130tN・5H
Calculated value as 20: C96515: H, 5, 11; N,
20.46 analysis value: 0.32.44:H, 2,84
;N, 16.59 Example 15 02H 7-[2-chloromethinone-2-(2-aminothiazol-4-yl)acetamide] -3-(1
,2,3-thiadiazol-5-yl)thiomesol-3
-Cephem-4-carboxylic acid (isomer A) was reacted according to the method of Example B, purified using Diaion HP20, and 7-[2-chloromethylene-2-(2-aminothiazole- 4-yl)acetamide]-3-(1
,2,3-thiadiazol-5-yl)thio,(f lu 3-cephem-4-carboxylic acid sodium salt (isomer A) was obtained.

Engineering R (KBr): 1760.1600.1530m
−'1JMRδ(d6-DMSO) : l 44 (
qAB, J -16Hz, 2H), 4.46(b
s, 2H), 5.06 (d, J-5H2゜IH)
, 5.61 (aa, J-5Hz, J-8H2, 1H)
.

6.45 (s, IH), 6.85 (s, IH), 7.
16(1) El.

IH), 9.07 (s, IH), 9.52 (d, J-8
Hz.

IH) Elemental analysis value 0xsH+zO6N604S4Na-2H
Calculated value as 20: C! , 3X42:H,2,81
:N, 14.62 Analysis value: C,51,86:H,2
,61:N,13.71 Example 16 HOt Haz 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide] -5-(1
,2,5-triazol-5-yl)thiomethyl-3-
Example 6 using cephem-4-carboxylic acid (isomer A)
7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1,
2,5-1-riazol-5-yl)thiomethyl-6-
Cephem-4-carboxylic acid sodium salt (isomer A) was obtained.

NMRδ (C6-nMso): S, 49 (qA
B, J -12'Hz, 2H), 4.07((IA
B, J-14H2, 2H), 5.06 (tl, J-5
H2, IH), 5.61 (act, J==SH2゜J
-8Hz, IH), 6.40 (s, iH), 6.82 (
θ, IH), 7.13 (bθ, 2H), 7.52 (θ,
1H), 9.53 (d, J-8Hz, IH) elemental analysis value (46H130LN704S3N&.2 H20 calculation): 0. 34.44:H, 3,0
7;N, 17.57 Analysis value: 0.32.40:H,
3,03;N, 15.31 Example 17 0zH 02Na 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-ro-(2-
Hydroxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (isomer A) was reacted according to the method of Example 6, purified using Diaion HP 20,
7-[2-chloromethylene-2-(2-aminof7zol-4-yl)acetamide]-3-(2-hydroxycarbonylmethylthio-1,3゜4-thiadiazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid disodium salt (isomer A) was obtained.

Engineering R (KBr): 1760.1600rm-'NM
Rδ(d6-DMSO): 3.49 (qAB,
J-18H2゜2H), 3.72(θ, 2H), 4
47 (qAB+ J ~ 12Hz, 2H), 5.07 (d
,,T-5Hz,IH).

5.63 (da, J-5Hz, J-8H2, IH).

6.43(θ, 1)I), 6.86(F3.IH
), 7.15 (be, 2H), 9.53 (a, J-8
Hz, IH) Elemental analysis value (4BH130tN6068
5 Na2” Calculated value as 4H20: 0.29.9
0; H, 2,93; N, 11.62 Analysis value: C!
,2a88:I(,2,65;N,10.88 Example 1
8 0zH 002N a 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide] -3-(2
, 5-dihydro-2-methyl-5-oxo-a8-triazin-3-yl)thiomethyl-3-cephem-4-carstonic acid (isomer A). 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2,5-dihydro-2-methyl-5-oxo -aθ-triazine-3
-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (isomer A) was obtained.

Engineering R (KBr): 1760.1610cm-'NM
Rδ (a6-nuso): A69 (sa, 2H)
, 4.27 (qAB, J-12H2,2H),
s, o 5 (a, J-7Hz, IH), 5.6
9(da, J=7)Iz, J-8I(z.

IH), A42 (Japanese, IH), A84 (s, IH).

7.12 (BS, 2H), 7.61 (Japan, IH), 9.
55 (cl, J-8Hz, IH) Elemental analysis value 0+s E+50 tN70583 N
Calculated value as a: 0.3a33:H, 2,68:N,
17.38 Analysis value: 0.32.19; H, A12
:N, 12.82 Example 19 Co2[ 9 2-chloromethinone-2-(2-,i-nylamylaminothiazol-4-yl)acetic acid z731 to ethyl acetate 25m
1 and cooled to -20°C, Vilsmeier reagent (
Under water cooling, phosphorus oxychloride z2- was added dropwise to DMF 1.77, heated at 50°C for 30 minutes, and then THF 25
) was added dropwise.

7-Amino-3,-(2-methoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid2. s s y was suspended in water 40-, saturated aqueous sodium bicarbonate solution was added thereto to dissolve it, and then THF 50 d was added.

The above solution was added dropwise to this solution under water cooling while adjusting the pH to 7.0 to 7.5, and stirred at the same temperature for 1 hour. The organic solvent was distilled off under reduced pressure, and after washing with ethyl acetate, the pH was adjusted to 5.5 with IN hydrochloric acid, the precipitate was separated, and then the pH was adjusted to 12. The precipitated crystals were collected, washed with water, and dried to give 7-C2-chloromethylene-2-(2-formylaminothiazole-4
Brown crystals of 2,56 f of 3-cephem-4-carboxylic acid were obtained.

0 methanol 337! To 22 m of THF and water-cooled stirring, 1.1-phosphorus oxychloride was added, and to this solution 7-
[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-methoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4 - 583 t of carboxylic acid was added and stirred at the same temperature for 1.5 hours. Next, the reaction solution was poured into ice water, adjusted to pHaO with a 10% aqueous sodium hydroxide solution, and washed with ethyl acetate.
It was set as H3.0. The precipitated crystals are collected, washed with water, dried, and 7-
[2-chloromethylene-2-(2-aminothiazole-
Brown crystals 2-849 of 4-yl)acetamido]-5-(2-methoxycarbonylmethylthio-1,5,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid were obtained.

After dissolving this in saturated sodium hydrogen carbonate hydroxide solution, HP
-20 column to obtain the sodium salt.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-methoxycarbonylmethylthio-1,3゜4-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid NMRδ(d6-DMSO): 3.67(s, 5H
), 4.37 (qAB, J-11H2,2H),
5. j 6 (d, J-5H2, IH), 5.76 (d
d,: f-5Hz, J-BH2゜th (), 6.58 (s
, IH), 6.82 (s, IB).

715 (be, 2H), 9.50 (d, :f-8H2,
IH) Example 20 C! 02H O◇ (6) 535 g of 2-rirometelene-2-(2-pormylaminothiazol-4-yl)acetic acid was added to 4 ml of dry THF.
Dissolve dicyclohexylcarbodiimide 2 under water cooling.
84 ~ was added and stirred for 2 hours. 7-amino-3-
(2-Carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4 to carboxylic acid 419++y was dissolved in 1 qmg of water, acetone 5- and a saturated aqueous sodium carbonate solution to adjust the pH to 6.

The above solution was added to this solution under water cooling, and after 45 minutes, the reaction solution was filtered, and the furnace solution was washed with ethyl acetate and then benzene.
The pH was adjusted to 6 with IN hydrochloric acid, the precipitate was separated, and the pH was further adjusted to 5.
And so. The precipitate was washed several times with water and dried to obtain 7-[2-chloromethylene-2-(2-formylaminothiazole-4
-yl)acetamido]-3-(2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid 46211v was obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetami)" ] -3-(
2-Carbamoylmethylthio-1゜3.4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid IJMRδ (a6-Duso): 4.00 (S, 2
H), 5.20((1,:J-5Hz, IH), 7.(
]5(s, 2H).

&47(s, IH), 9.56(a, J-8Tlz, I
H) ■ To 2.8- of dry methanol and 2.5- of dry THF, add phosphorus oxychloride, 22-, while stirring on ice, and add 7-[2-chloromethylene-2-(2) to a vinegar solution of -formylaminothiazol-4-yl)acetamide]-5-(
580 2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-6-se7emu-4-carboxylic acid was added and stirred at room temperature for 1 hour.

Ethyl acetate and water were added to the reaction solution, the pH was adjusted to 7 with a saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 3.2 after washing with ethyl acetate and then benzene.

The precipitate was washed several times with water and dried to give 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-carbamoylmethylthio-1,3,
190 ml of 4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid were obtained.

After dissolving this in saturated sodium hydrogen carbonate aqueous solution VC,
Purification was performed using an HP-20 column to obtain a sodium salt.

7-[2-chloromethinone-2-(2-aminothiazol-4-yl)acetamide]-3=(2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4- Carboxylic acid NMRδ (cl, -DMSO): 3.68 (bs,
2H), 4.00(s, 2H), s, 17(a, J-
saz, IH).

5.76 (ad,, T-5H2, J-8H2, IH),
&40 (8, IH), 6.85 (Japan, IH), 9.50
(d, J=8H2, IH) Example 21 02H 9→ j9 In the method of Example 20, 7-amino-1-(2
7-amino-3-(2-acetylamino-
1,3,4-thiadiazol-5-yl)thiomethyl-
Using 387μ of 3-cephem-4-carboxylic acid, the same operation was performed to obtain 7-[2-chloromethylene-2-(
456 yellow crystals of 2-formylaminothiazol-4-yl)acetamido]-3-(2-acetylamino-1,he4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid were obtained. .

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-acetylamino-1,3,4-thiadiazol-5-yl)thiomethyl-6-cephem- 4-Carboxylic acid engineering R (KBr): 1770.1670, l540c
y-'NMRδ(d6-DMSO): 2.20(e
, 3H), 3.68 (bs, 2H), 4.51 (
qAB, J = 1 4Hz, 2H).

5.16 (d, J-5Hz, IH), 5.76 (
d, d, J-5H2, J-8H2, IH), 6.59
(θ, IH).

6.83 (e, IH), 7.09 (bs, 2J (
), 9.51 (d, J-8H2, IH) amat ΩQ To 27.4 m of methanol, 27.4 tnl of THF and 2.74 m of water, 5.0 - of concentrated sulfuric acid was added dropwise, and to this solution was added 7-[2 -chloromethinone-2-(2-formylaminothiazol-4-yl)acetamide 3-5-(2-acetylamino-1,3,4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid 5 .5
f was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, adjusted to pH 7:2 with 28% ammonia water, and washed with ethyl acetate. Under reduced pressure, ethyl acetate in the aqueous layer was distilled off, the pH was adjusted to 5.5 with 1N hydrochloric acid, and insoluble matter was separated in a furnace, 1)
1 (set to 5,1). The precipitated crystals were washed with water, dried, and
-[:2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide 3-5-(2-acetylamino-1,3,4-thiadiazol-5-yl)thiomethyl-6-cephem-4 - Yellow crystals of carboxylic acid 4.1
I got 07.

After dissolving this in saturated sodium hydrogen carbonate hydroxide solution, H
Purification was performed using a P-20 column to obtain a sodium salt.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-acetylamino-i, 3.4-thiadiazol-5-yl)thiomethyl-3-cephem-4 -Carboxylic acid engineering R (KBr): 1770.1660.1620.
1530cm'NMRδ (a6-DMso): 2°20 (s, 3H), 3.68 (bs, 2H), 4.
51 (qAB, J-14Hz, 2H).

5.16 (d, J-5Hz, IH), 5.76 (ad,
J-5Hz, J-8Hz, IH), 6.39(s, IH
).

b, a 3 (θ, IH), 7.09 (be, 2H)
, 9.51 (d, J-8H2, IH) Example 22 02H U'/) 0 Pass In the method of Example 20 above, 7-amino-3-(2
-Carbamoylmethylthio-1,44-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid instead of 7-amino-3-(2-ethoxycarbonyl-1,3,4-thiadiazole-5- yl)thiomethyl-3-se7em-4-carboxylic acid 402q, the same operation was performed to obtain 7-(2-chloromethylene-2-
(2-formylaminotheasol-4-yl)acetamide, ]-3-(2-ethoxycarbonyl-j, 3.
520 light brown crystals of 4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-ethoxycarbonyl-1,3,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (KBr) + 1775.1740.1715.
1660.1625.1530crn-1 NMRδ(d6-DMSO): 155 (t, J
-7H2,5H).

5.71 (bs, 2H), 4.33 (d, J-14Hz
, IB), 4.41 (q, J-7Hz, 2H), 4.7
0(d.

J-14Hz, IH), 5.18(d, J-5Hz, I
I().

5.80 (d4.J-5Hz, J-8Hz, IH).

6.44 (8, IH), 6.85 (s, IH), 9.5
1(d, J-+8Hz, IH) In the method of Example 21 above, 7-(2-chloromethinone-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-acetylamino- 1,3
, 4-thiadiazole-5-(l)thiomethyl-3-cephem-4-carboxylic acid, 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3- (2-ethoxycarbonyl-
1,44-thiadiazol-5-yl)thiomethyl-3
-Cephem-4-carboxylic acid &66f was used, and the same operation was carried out.
aminothiazol-4-yl)acetamide]-3-(
2-ethoxycarbonyl-1,4-theadiazole-
2.441 light brown crystals of 5-(l)thiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(2-ethquinecarbonyl-1,5,4-thiadiazol-5-yl)thiononal-3-cephem- 4-Carboxylic acid engineering R (KBr): 1770.1740,1720.
1665.1545Crn-' NMRδ(d6-DMSO): 1.35(t, J-7
Hz, 5. H).

3.71 (bs, 2H), 4.33 (d, J-1
4H2, IH), 4.41 (q,, J-7H2,2
H), 4.70 (d.

J-14111Z, IH), 5.18(a, J-
5H2, 1H), 5.80 (da, J-5H2, Js-
8Hz, IH).

6.44 (s, IH), 6.85 (e, IH), 9.5
1 (tL, J-8Hz, IH) of V 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamido]-3-(2-ethoxycarbonyl-1,5,4-thiadiazole) -5-yl)thiomethyl-6-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution, purified by applying it to an HP-20 column, -yl)acetamido]-3-(2-ethoxycarbonyl-1,3,4-thiadiazole-5-
yl)thiomethyl-5-cephem-4-carboxylic acid sodium and 7-[2-chloromethylene-2-(2-aminothiazol-4-yl]acetamide]-3-(2-carboxy-1,S, 4- thiadiazol-5-yl)
Disodium thiomethyl-3-cephem-4-carboxylate was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-carboxy,-1,3,4-theadiaso-5-yl)thiomethyl-6-cephem -4-Carboxylic acid disodium NMRδ (d6-DMSO): 3.4 B (qA
B, J = 17Hz, 2H), 4.43 (qAB, ,
T-13H2, 2H), 5.25 (J, J-5Hz, I
H), 5.60(+1(1, J-5, Hz.

J-8H2, IH), 6.39 (S, IH), &82 (
8゜IH), 7.10 (bs, 2H), 9s2 (a, J
-8Hz, IH) Example 23 CHO4 In the method of Example 20 above, 7-amino-3-(2
7-amino-5-(2-amino-1
,5,4-thiadiazol-5-yl)thiomethyl-6
Using 3451 ng of -cephem-4-carboxylic acid, the same operation was carried out, and 7-[2-chloromethylene-2-(
2-formylaminothiazol-4-yl)acetamide]-3-(2-amino-1,44-thiadiazole-
450 pieces of pale brown crystals of 5-yl)thiomethyl-3-cephem-4-carboxylic acid were obtained.

(Incorporated) In the method of Example 21, 7-[2-chloromethinone-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-acetylamino-1,
7-[:2-chloromethylene-2-(2-formylaminothiazole-4-
yl)acetamido]-3-(2-amino-1゜3.4
-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid 785f, the same operation was carried out, and 7-[2-chloromethylene-2-(2-aminothiazol-4-yl) acetamide] -3-(2-
ik of amino-1゜3.4-thiadiazol-5-yl)thiomethyl-3-cephem-4-cardoic acid? a
Color crystals 2,799 and its sodium chloride were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-amino-1
,3,4-thiadiazole-5-(l)thiomethyl-5
-cephem-4-carboxylic acid NMRδ (a6-+:+Mso): 3.66 (bs
, 2H), 5.13 (d, J=5Hz, IH), 5.7
5 (ad, J-5H2゜J-8Hz, IH), 6.38
(s, IH), 6.82 (s, IH), 9.48 (d,
J-8H2, IH) Example 24 02H (fn (4) In the method of Example 20, 7-amino-3-(2
-carbamoylmethylthio-1,44-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-amino-3-(2-diethylaminoethylthio1,44-thiadiazole-5-yl) yl)thiomethyl-6-cephem-4-carboxylic acid 461rnV, the same operation was carried out, and 7-[2-chloromethylene-2-(,2-formylaminothiazol-4-yl)acetamide]-3- Light brown crystals of (2-diethylaminoethio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 322
We obtained η.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetami)' ] -3-(
2-diethylaminoethylthio-1,44-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid R (KBr): 1770.1670.1540c
m'NMRδ ((16-DM80): 1.13(t
, :J-7H2,6H).

2.93 (q, J-7Hz, 4H), ! x16(
bs, 2H).

3.50 (bs, 2H), 3.62 (qAB, J-17
H2゜2H), 4.35 (qAB, J-15Hz,
2H), 5.17 (d, J-5Hz, IH), 5.
75 (dd, J-5Hz.

J-8H2, IH), 7.03 (e, IH), 7.06
(s.

1H), 9.65(d,, T-8i(z, IH), 12
．． 4 (bs, IH)) In the method of Example 21 above, 7-(2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamido]-3-(2-acetylamino-1, 3
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-(2-chloromethylene-2-(2-formylamiJf-azole-4-
yl) acetamide,]-3-(2-diethylaminoethylthio-1,44-thiadiazol-5-yl)thiomethyl-6-se7em-4-carboxylic acid 555f, and the same operation was performed to obtain 7- [2-chloromethylene-
2-(2-aminothiazol-4-yl)acetamide]-3-(2-diethylaminoethelthio-1,44-
Light brown crystals of 1,50 f of thiadiazol-5-yl)thiomethyl-3-cephem-4-fulponic acid and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-5-(2-dietheraminoethertheo1.3.4-thiadiazol-5-yl)thiomethyl-3-cephem -4-Sodium carboxylate NMRδ (+16-DMEIO): 2.1o(t,
J-=8Hz, 6H).

2.86 (q, J-8H7, 4H), 105 (bt, 2
H).

5.42 (bt, 2H), 3.60 (qAB,, T-1
8Hz.

2) (), 4.35 (qAB, J-14H2, 2H),
5.16 (a, J-5Hz, IH), s, 7:z (aa
, J-5H2゜J-8H2, IH), &2.0(s, I
H), 6.83 (e, ta), z18 (bs, 2H)
, 9sa(a,;r-8H2,IH) Example 25 02H) In the method of Example 20 above, 7-amino-3-(2
-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid instead of 7-amino-3-(2-carbamoyl-
1,3,4-thiadiazol-5-yl)thiomethyl-
Using 376 μ of 6-cephem-4-carboxylic acid, the same operation was performed to obtain 7-(2-chloromethylene-2-(
2-formylaminothiazol-4-yl)acetami)" 3-s-(2-carbamoyl-1,5,4-
630 cm of pale brown crystals of thiadiazol-5-yl)thiomethyl-5-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-polmylaminothiazol-4-yl)acetamide]-5-(z-carbamoyl-1,3,4-thiadiazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid NMRδ (d6-DMSO): 3.68 (qAB
, J-18H2,2H), 4.47(qAB, J
-14klB, 2H), 5.18 (+1. J-5H2
,IH),s,ao(aa,,T-5H2゜J-8Hz
, IH), 7.04 (8, IH), 7.07 (s, IH
), a13 (s, IH), a51 (s, 2H), 9.6
6 (d, J-8Hz, IH), 12.47 (bs, I
H) ... In the method of Example 20, 7-[2-chloromethinone-2-(2-formylaminotheazol-4-yl)acetamide]-3-(2-carbamoylmethylthio-1,3,4-thiadiazole) -5-yl)thiomethyl-6-cephem-4-carboxylic acid, 7-[2-
Chloromethylene-2-(2-pormylami/-7-azol-4-yl)acetamide]-3-(2-carbamoyl-1,44-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 7 Using .94 f, the same operation was performed to obtain 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-carbamoyl-1,44-thiadiazole- 5.78 W of pale brown crystals of 5-yl)thiomethyl-3-cephem-4-carboxylic acid and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(2-carbamoyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4- Carboxylic acid NMRδ (a6-DMso): 587 (bs, 2H
), 4.48 (qAB, J= j 3H2,2H), 5
．． 22 (d, J-5Hz, IH), 5.81 (dd, J
-5Hz, J-BH2゜IH), 6.41 (s, IH)
, 6.85 (s, IH).

7.13 (bs, 2H), alo (bs, IH), 8.
45 (bs, IH), 9.53 (d, J=8Hz, IH
) Example 26 o2H <61 (7-amino-3-(2
-Carbamoylmethylthio-1,5,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid instead of 7-amino-6-(2-hydroxymethyl-1,3,4-thiadiazole- Using 359 μl of 5-yl)thiomethyl-3-cephem-4-carboxylic acid,
Following the same operation, 7-(2-chloromethylene-2
-(2-formylaminothiazol-4-yl)acetamide 3-3-(2-hydroxymethyl-1,he4-thiadiazol-5-yl)thiomethyl-3-cephem-
438 cm of yellow crystals of 4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-X-(Z-hydroxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem- 4-Carboxylic acid engineering R (KBr): 3220.1760.1660z
-'NMRδ(d6-DM80): 3.7(bs,
2H), 4.46 (qAB, J-15Hz, 2H)
, 4.8 (6,2H).

s, 1y (a, J-5Hz, 1n), s, al (aa,
, r-5Hz, T-8Hz, IH), 7.05 (g
, 2H).

as(s, IH), 9. S? (a, J-8Hz, IH
) Q → In the method of Example 20, 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-carbamoylmethylthio-1,3,4-thiadiazole -5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-(2-
Chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(2-hydroxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid a45F 7-[2-chloromethylene-
2-(2-amituteazol-4-yl)acetamide]-3-(2-hydroxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-5-cephem-4-
Brown crystals of carboxylic acid &342 and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(2-hydroxymethyl-1,he4-thiadiazol-5-yl)thiomethyl-3-cephem-4- Carboxylic acid engineering R (KBr): 3300. 1765.1650
Crn-'NMRδ(da-DMSO): 5.67
(be, 2H), 4.42 (qAB,, T-1!
IHz, 2H), 4.8 (8, 2H).

5.17(d, J=5H2,IH), 5.80((
1 (1, J=5Hz, J-8Hz, 1H), 6.50(
e, jH).

&85(8,IH),s+,52(a,J-8H2,I
H) Example 27 In the method of Example 20 above, 7-amino-3-(2
-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-amino-3-(1-sulfonotyl-
The same operation was carried out using 408 μl of 1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, and after dissolving it in a saturated aqueous sodium bicarbonate solution, it was purified by applying it to a UP-20 column. 7-[2-,70rometelene-2-(2-*lumylaminothiazole-4-
il) acetamide] -! l-(1-sulfomethyl-1
Colorless amorphous crystals of disodium H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate 70
I got 0■.

In the method of Example 21, 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamitoco-3-(2-acetylamino-1,he4-thiadiazol-5-yl) As a representative of thiomethyl-3-cephem-4 carboxylic acid, 7-(2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(1-sulfomethyl-1H-tetrazol- 5-yl)thiomethyl-6-cephem-4
- Using 4.8 t of disodium carboxylate, the same operation was carried out, and 7-[2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamide]-5-(
1.87 r'f of disodium 1-sulfomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-sulfomethyl-1H-tetrazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid disodium NMRδ(d,-DMSO): i51 (qAB,
J = 18H2, 2H), 4.29 (qAB, J =
13H2, 2H), 5.00 (s, 2H), 5.06 (
d, J-5H2, IH), 5.63 (aa,, T-5H
z,: r-sHz, IH), 6.39 (S.

IH), 6.82 (s, IH), Z15 (e, 2H).

9.55 (d,, T-8Hz, IH) Example 28 02H (2) JMU In the method of Example 20, 7-amino-3-(2
-carbamoylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid, 7-amino-5-(I H-1,2,4
Using 613q of -triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid, the same operation was performed to obtain 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl) acetamide) -3-
655 ml of (I H-1,2,4-1-riazol-3-yl)thiomethyl-5-cephem-4-carboxylic acid were obtained.

1 In the method of Example 20, 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-6-(2-carbamoylmethylthio-1,44-thiadiazol-5-yl) )thiomethyl-
3-cephem-4-carvone, instead of acid, 7-[2
-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(IH-1,2,
Using 4-triazol-6-yl)naomete-3-cephemu-4-carvone 7739', the same operation was performed to obtain 7-[2-chloromethylene-2-(2-aminothiazol-4-yl]acetamide] -3-(I
H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid 1.95 F and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(I H-12,
4-) Riazol-3-yl)thiomethyl-6-cephem-4-carboxylic acid NMRδ (d6-DMSO):
l 65 (qAB, J-18H2,2H), 4
．． 17 (qAB, J-13Hz, 2H), 5.1
5 (a, J-5Hz, IH), s, 76 (aa,, T-
5Hz.

J=8Hz, IH), ls, 40 (El, IH), 6.
85 (S.

IH), 7.20 (bs, 2H), 8.45 (bs, I
H).

9.57 (d, J-8Hz, IH) Example 29 002HH (/I Qυ In the method of Example 20, 7-amino-3-(2
-carbamoylmethylthio-1,5,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid ((JK, 7-7minor 3-(3-amino-IH
-1,2,4-triazol-5-yl)thiomethyl-
Using 3-cephem-4-carboxylic acid 328~, the same operation was performed to obtain 7-[2-chloromethylene-2-(
3861 fPg of 2-formylaminothiazol-4-yl)acetamido]-3-(3-amino-1H-1,2,4-)lyazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid was obtained.

) In the method of Example 21, 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-5-(-2-acetylamino-1,
7-(2-chloromethylene-2-(2-formylaminotheazol-4-yl)acetamide]-3 instead of 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid -(s-amino-I H-1,
The same operation was performed using 4.1°V of 2,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid to obtain 7-(2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamide]-? 1-
(3-amino-I H-1,2,4-)lyazole-5
2.94f of pale yellow crystals of (-yl)thiomethyl-3-cephem-4-carboxylic acid and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3-amino-I
Sodium H-1,2,4-)riazol-s-yl)thiomethyl-3-cephem-4-carboxylate NMRδ (D20): ! 1j8(d, J-18H2
, IH).

3.73 (d, J-14Hz, IH), &79 (d, J
-18Hz, IH), 4.25(d,, T-14H2,
IH).

5.18 (cL, J-5Hz, IH), 5.77 (d,
J-5HE, IH), &64(8,1n), 6.97(
[1, IH) Example 30 02H 3 (lΦ 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid (isomer A) (7,44f, 31
mmo4) was dissolved in THF (40d), and D
CO (5.95f, 19 mmot) was added and stirred at the same temperature for 2 hours. On the other hand, 7-amino-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4,85f, 14m
Moj) was suspended in a mixed medium of water-acetone (95d-40m/), cooled to 0°C, and then an aqueous sodium bicarbonate solution was added to adjust the pH to 7.4. The previously prepared acid anhydride solution was added dropwise to this reaction solution. After dropping, the mixture was stirred at the same temperature for 1 hour. The precipitate was filtered and water (50ml) was added to the p solution. This solution was washed with ethyl acetate. The aqueous solution was cooled with ice, and then adjusted to pH 3.0 using 2N hydrochloric acid. The precipitate was separated and dried. 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl]acetamide]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3- as a powder Cephem
4-carboxylic acid (7,2r) was obtained.

NMRδ(d6-DM80): 2.50(s, 3
H), 3.66((IAB, J-18Hz, 2H
), 4.43 (qAB, J-15H2, 2H),
5.21 (d, J-4,5Hz, LH).

5.78(ad, J-4,!5Hz, ,T-9I(
Z, IH).

zoo(s, 1.H), 7.01(s, IH), 9.6
6(d, J-9Hz, IH) q$ 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-5-(5-methyl-1,2,4-thiadiazole -5-yl)thiomethyl-6-cephem-4-carboxylic acid (isomer A) (1
21,12,8m m0L) in methanol-THF (
1: 1. ' Dissolved in 80ml of mixed vinegar medium, 0 to 5
Cooled to ℃. Phosphorus oxychloride (2,94f, 19mm
ot) was added dropwise and stirred for 2 hours. After the reaction, saturated sodium bicarbonate solution was added and I) H! h, I set it to O. The solvent was distilled off under reduced pressure, the pH of the residue was again adjusted to 2.5, and the precipitate was filtered and dried. 7-[2-chloromethylene-
2-(2-aminothiazol-4-yl)acetamide]-3-(3-methyl-1゜2.4-thiadiazole-
5-yl)thiomether-3-cephem-4-carboxylic acid (J1 body A) (5,921) was obtained as a powder.

NMRδ(d6-DMSO) + 2.50 (s,
3H), 5-66 (qAB, J-18H2, 2u
), a, 4s (qAB, J-15H2, 2H),
5.20 (d, J-4, 5Hz, IH).

5.79 (act, , T-4, 5H2, J-9Hz,
IH).

6.43 (8, IH), &89 (8,1H), 7.20
(bs, 2H), 9.66 (d, J-9Hz, IH) f
→ 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3-methyl-1
,2,4-thiadiazol-5-yl)thiomethyl-3
A saturated aqueous sodium bicarbonate solution was added to -cephem-4-carboxylic acid (isomer A) (sr) to give a solution with a concentration of 7.4% (I). This rock liquid was purified by passing it through a Diaion HP20 column, and purified with 7-[2-chloromethylene-2-(2
-aminothiazol-4-yl)acetamide]-3-
(3-Methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (isomer A) (tsy) was obtained as a white powder.

NMRδ(a6-DMso): 2. s s (Sunday, 3H), 3.48 (qAB, J-17Hz, 2H
), 4.50 ((IAB, J-12Hz, 2H),
s, o7 (a, J-5H2, IH).

5.65 (da,, T-5Hz, J=8, IH), &
44 (Japanese, IH), 6.86 (Japanese, IH), 7.16 (
b8. 2H), 9.50 (d, J-8Hz, IH) Example 31 HO1 Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminotheasol-4-yl)acetamide ]-3-[1-(IH-tetrazol-5-ylmethyl)-1H-tetrazol-5-ylcutiomethyl-3-cephem-4-carboxylic acid sodium (isomer A
) was obtained.

NMRδ(d6-DMEIO): 3.50 ((I
AB, J-18Hz.

2H), 4.52 (qAB, J-12H2,2H
), 5.09 (cl, J+-5H2, IH), 5.6
0(8,2H).

5.64 (d4.J-5, 8H2, IH), &4! +(
s, IH), 6.86 (s, IH), 7.16 (bs,
2H).

9.54(d,,J-8H2,IH) Example 32 Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl]acetamide]-s- [1-(2-dimethylaminoether)-1
H-tetrazole-5-(l)thiomethyl-3-cephem-4=sodium carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO): 2.15 (s,
6H), 2.68 (t.

176H2, 2H), 3.40 (qAB, J-1
0H2,2H), 4.36(qAB, J-12Hz
, 2H), 4.37(t,:f=6Hz, 2H),
5.05 (d, J-5Hz, IH), 5.63 (ad2
．． T=5Hz, J-8H2, IH).

6.44 (e, IH), 6.86 (s, IH), 7.1
7 (bs, 2H), 9.48 (cl, J-8Hz, IH
) Example 33 Following a method similar to Example 6, 7-[2-chloromethylene-2(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-4-pyridiniothiomethyl)
-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ (d6-DMSO): 140 (qAB,
2H), 4.22 (s, 3H), 4.25 (qAB
, 2H), 5.21 (d.

J-5H2, IH), 5.44 (ad, +T+5Hz,
Jx8Hz, IH), 6.42 (s, IH), 6.91
(e, IH), 7.17 (bs, 2H), 7.60 (d
, J-7H2゜2H), aa2(a,, T-7H2,2
H), 9.52 (a.

J=8H2, IH) Example 34 o2H HC1 1 C! 02 N a Following a method similar to Example 6, 7-[2-chloromethylene-2-ζ2-aminothiazol-4-yl]acetamido]-3-(2-pyridyl)thiomethyl-3-cephem-4-carvone 3, NMR δ (d6-DMSO): 159 ('IAB
+ J -18Hz, 2H), 4.37 (qAB, J
-12H2,2H), 5.02(a, J, -5H2,
IH), 5.56 (ad, J-5H2゜J-8H2
, IH), 6.42 (8, IH), 6.83 (s.

IH), 7.08 (t, J-5Hz, IH), 7.12
(bs, 2H), 7.38 (d, J-7H2, IH).

7.64 (t, J-7Hz, IH), a42 (t, J-
5Hz, IH), 9.44 (d, J-8Hz, IH) Example 35 Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide ]-3-(pyrimidin-2-yl)thiomethyl-3
Sodium -cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO)+3.17~&66
(m, :?H).

4.35 (qAB, J= 13H2,2H), 5.0
6((1,J-5H2,IH),s,+5(aa,,T
-5H2, J-8Hz, IH), 6.42 (s, IH)
, +S, 84 (8, IH).

Z12 (be, 2H), Z2o (t, J-5H2, 1H
).

8.63(a, J+=5H2,2H), 94x(a,
J-8Hz, IH) Example 36 Co, H 02Na Following the same method as in Example 6, 7-[2-lyloromethylene-2-(2-aminotheazo-4-yl)acetamide]-ro-(5 -carboxinmethyl-4-methyl-
Disodium 1,3-thiazol-2-yl)thiomethyl-5-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(a6-DMso): 2.16 (θ, 3
H), 524 (e.

2H), 4.32 (qAB, J-12H2, 2H)
, 5.0! +((1,, J-5Hz, 1st), 5.
60 (dd,:f-4Hz.

J-14H2, IH), &44(s, IH), &86(
s.

IH), 7.14 (bs, IH), 9.48 (d,,T
=8H2,IH) Example 37 02H Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-amino-y-azol-4-yl)acetamide]-3-(5-carbamoyl Methyl-4-methyl-1,3-thiazole-2-(l)thiomethyl-3-
Sodium cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO): 2.23(s, 3
H), 3.45 ((IAB, J-17Hz, 2H),
3.55 (s, 2H).

4.32 (qAB, J = 12H2,2H), 5
．． 04(d.

J-5Hz, IH), 5.61 (dd, J-5Hz, J
-8H2, IH), 6.44 (S, iH), &86 (s
, IH), 7.04 (be IH), 7.15 (b day +
"") +7.58 (bS, iH), 9.48 (d, J-
8H2, IH) Elemental analysis value: C26HHOtN605
Calculated value as S4Na-H2O 0:3a31 H:1
21 N; 1a40 analysis value 0:36.35 H:3.
15 N: 12.73 Example 3 Day Hat Co, H Following a method similar to Example 20, 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide-3-(5- Ethoxycarbonylmethyl-1,4
Sodium 4-thiadiazol-2-yl)thiomethyl-5-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d4-DMSO): 3+01(t, J
-7Hz, 3H).

3.47 (qAB, J-17H2, 2H), 4.1
6 (q, J-7Hz, 2H), 427 (e, 2H),
4.46 (qAB.

J-12H2, 2H), 5.05 (d, J-5H2, I
H).

5.61 (da, J-5Hz, J-8H2, IH
), 6.42 (e, 1u), 6.84 (8, IH),
713 (be, 2H), 9.46 (d, J=8H2, I
B) Elemental analysis value: 02 (l H2S 0 tN606
Calculated value as s4 Na-H20 0:57.35
H; 3.13 N; 13.07 analysis value 0; 35.9'
8 H: 3.08 N: 12.77 Example 39 02H Vj) (c) 2-chloromethylene-2-(2-*lumylaminothiazol-4-yl)acetic acid (isomer A) (7,5 , 32m
m0t) in THF (40 ml) and cooled on ice.
Add DOC (4.04f, 19.6 mmot),
The mixture was stirred at the same temperature for 2 hours. On the other hand, 7-amino-3-(
5-Carbamoylmethyl-j, 3.4-thiadiazol-2-yl)thiomethyl-6-cephem-4-carboxylic acid (5,18f.

13 mmol) in water-acetone (ssy-32y
), and after cooling to 0° C., a sodium bicarbonate hydroxide solution was added to adjust the pH to 7.4.

The previously prepared acid anhydride solution was added dropwise to this reaction solution. After dropping, the mixture was stirred at the same temperature for 3 hours.

Since the pH of the reaction vinegar solution was 5.1, an aqueous sodium bicarbonate solution was added to adjust the pH to 7.0. After filtration and washing the tear fluid with ethyl acetate, the organic solvent was distilled off under reduced pressure.

Using 2N hydrochloric acid to make I) H2,5, the precipitate was filtered and dried to give 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(
5-carbamoylmethyl-1,44-thiadiazole-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (isomer A) (&91f, 86%) was obtained.

NMRδ (a6-:oMso): 566 (bs,
2H), 3.98 (bs, 2H), 4.57 (qAB
, J = 12H2,2H).

5.17 (d, :J-4Hy, IH), 5.72 (m,
IH).

ZOO (e, iH), 7.27 (bs, IH), 7.
68 (bs, IH), a22 (s, IH), 9.55 (
(1°J-8Hz, IH) Gu7-[2-chloromethinone-2-(2-formylaminothiazol-4-yl)acetamide]-3-(5-carbamoylmethyl-1,5,4-thiadiazole-2 −
yl)thiomethyl-6-cephem-4-carboxylic acid (isomer A) (6,q y, 11.5 mmot) was suspended in a mixed solvent of methanol-THF (1: 1,80 m/) and heated at 0 to 5 °C. It was cooled to Phosphorus oxychloride (3,53F.

23m mot) was slowly added dropwise at the same temperature, and the mixture was further stirred at the same temperature for 2 hours. After the reaction, ice water and a saturated aqueous sodium bicarbonate solution were added to adjust the pH to 2.5. The solvent was distilled off under reduced pressure, the pH of the residue was confirmed to be 2-7, and the precipitate was filtered, washed with water, and dried. 7-(2-ri0 lometerene-
2-(2-aminothiazol-4-yl)acetamide]-3-(s-carbamoylmethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (isomer A) (6,1F) was obtained as a powder.

NMRδ (d6-DMSO): 165 (bs,
2H), 197 (B, 2H), 4.53 (qAJ
3. J-12Hz, 2H).

s, 1o (a, J-4H2, IH), 5.68 (m, I
H).

6.25 (8, IH), &73 (s, IH), 7.15
(BS, 1H), 7.72 (BS, IH), 9.58
(d.

J-8H2, IH) HO1 So7-[chloromethylene-2-(2-(2-aminothiazol-4-yl)acetamido]-3-(5-carbamoylmethyl-1,5,4-thiadiazol-2- )
Thiomethyl-6-cephem-4-carboxylic acid (isomer A
) (34) was added with a saturated aqueous sodium hydrogen carbonate solution, and p
A solution of H7.4 was obtained. The solution was purified by passing through a HP 20 column and 7-(2-chloromethylene-2-(
2-aminothiazol-4-yl)acetamide]-3
-(5-carbamoylmethyl-1,3,4-thiadiazol-2-yl)thiomethyl-5-cephem-4-carboxylic acid sodium salt (1,68?) was obtained as a white powder.

NMRδ (d6-DMSO): X46 (qAB,
J-18H2゜2H), 4.00(θ, 2H),
4.42 ((JAB, J-12H2, 2H), 5.
04(d,:f-4H2,iH).

5.60 (da, J-4Hz, J-8Hz, IH).

6.41 (s, IH), &84 (s, IH), 7.12
(be, 2H), 7.28 (1) S, IH), 7.8° (bs, IH), 9.46 (d, J-8H2, IH) Example 40 DMF (0,71r) K, Under ice cooling, phosphorus oxychloride (t 19 y ) was added. The mixture was heated at 50°C for 30
Stir for minutes, dilute with THF (15+++/),
2-rit:I lometelene-2-(2-formylaminothiazol-4-yl)acetic acid (isomer A) (ts 1y
) in ethyl acetate (15,t) suspension at −25° to −
Added at 20°C. After stirring at the same temperature for 10 minutes, -4
Cooled to below 0°C.

(6R,7R)-7-amino-3-(1-pyridiniummethyl)-3-cephem-4-carboxylic acid dihydrochloride (2
, 56r) in water (25 e) and acetone (50+++
Add a 20% potassium carbonate aqueous solution to the solution to adjust the pH.
Adjusted to 7.5~aO.

The above acid chloride solution was added to this aqueous solution at 0° to 5°C while maintaining pn at 15 to aO.

After stirring at the same temperature for 30 minutes, the solvent was distilled off (pH 5, 7
). The pH of the remaining aqueous solution was adjusted to 7, water was distilled off to dryness, and the solution was vacuum-dried over phosphorus pentoxide.

This dry matter was mixed with methanol (30-) and human THF (30 m
/), and phosphorus oxychloride (4,97V) was added under water cooling. After stirring at the same temperature for 1 hour, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7, and the solvent and water were distilled off to dryness. This was purified by applying it to an HP-20 column. The aliquots distilled with 20% ethanol-water heart fluid were collected and lyophilized to give (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-chloromethinoneacetamide]-3- (1-pyridiniummethyl)-5-cephem-
4-carboxylate (isomer A) (200mV)
I got it.

NMRδ (d6-DMSO): 151 (qAE,
J=18H2,2H), 5.14(d, J-5Hz
, IH), 5.73 (dd.

J=-5H2,, T-8H2, IH), /), 40(e
, IH).

6.84 (s, IH), 7.15 (br, s, 2H).

a4o (t, J-5, 5Hz, 2H), a4a ~8.
76 (m, IH), 9.21 (d, J-5,5Hz, I
H).

9, ri6-9.68 (m, 2H) Example 41 HO1 HC1 In Example 21, 7-[2-chlorolfV-2-(
2-aminothiazol-4-yl)acetamide]-3
-(2-acetylamino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carvone
-(2-amituthiazol-4-yl)acetamide]
7-[2-chloromethylene-
Sodium 2-(2-aminothiazol-4-yl)acetamido]-3-(1,2,4-triazol-1-yl)methyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO): 3.53 (qAB
, J -18Hz.

2H), 5.06 (d, J-5Hz, IH), 5.10
((IAB, J-14H2, 2H), 5.64 (
dd, J-5H2, Jw8Hz, IH), 6.41(
s, 11().

6.84 (s, IH), 714 (bs, 2H), 7.9
4 (s, IH), a64 (s, IH), 9.47 (d,
J-8Hz, IH) Example 42 In Example 21, 7-[2-chloromethylene-2-(
2-aminothiazol-4-yl)acetamide]-3
-(2-acetylamino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carvone
2-(2-aminothiazol-4-yl)acetamido]-s-(1,2,4-thiadiazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid (isomer A
), the same operation was performed to obtain 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(1,2,4-thiadiazol-5-
Sodium yl)thiomethyl-6-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO): ! L47 (11AB
, J=17H2,2H), 4.54((IAB,
J-12H2, 2f(), 5.06(+1.J-5H
z, IH), 562 (aa, J-5Hz.

J=8Hz, IH), 6.43 (8, IH), 6.85
(s.

IH), 714 (bs, 2H), a70 (s, IH).

9.49 (a, J-8Hz, IH) Example 43 H3 4-methyl-5-trifluoromethyl-4H-1,2,
4-triazoline-3(2H)-thione 4,58 and 6.82 of 7-amitusephalosboranic acid were suspended in 50 of acetonitrile, and after adding 9.73 of methanesulfonic acid, at 55°C. Stirred for 2.5 hours. Then,
Under water cooling, add 50% of water and adjust to pH 6 with concentrated ammonia water.
And so. The precipitated crystals are alluvially deposited, washed with water, dried, and 7-amino-
3-(1-methyl-2-trifluoromethyl-I H-
i, 4-triazol-5-yl)thiomethyl-6-
Light brown crystals of cephem-4-carboxylic acid &571 were obtained.

7-amino-3-(1-methyl-2-trifluoromethyl-I H-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid NMRδ (D20+0F3000H): 3.90
(bs, 2H).

4.03 (s, 3H), 4.55 (qAB, J-14H
2゜2H), 5.42 (bs, 2H) → + (c) → (a) In the method of Example 20, 7-amino
3-(2-carbamoylmethylthio-1,5,4-thiadiazol-5-yl)thiomethyl-5-se7emu4
- In place of carboxylic acid, 7-ami/-! +-(1-methyl-2-trifluoromethyl-I H-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid 696~ was followed by the same operation to obtain 7-[2-riooytterene-2-(2-formylaminothiazol-4-yl)acetamide]-5-(
1-methyl-2-trifluoromethyl-IH-1,3,
Light brown crystals 392 of 4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethinone-2-(2-polmylaminothiazol-4-yl)acetamide]-3-(1-methyl-2-trifluoromethyl-I H-t 5.4-
triazol-5-yl)thiomethyl-5-cephem-4-carboxylic acid NMRδ(d6-DMSO): A
68 (s, 5H), 4.22 (be, 2H), 5.
20 (d, :r-5Hz, IH).

585 (dd, J-5Hz, J-8Hz, jH), 7.
06 (s, 2H), EL52 (s, IH), 9.65 (
a, J-8Hz, IH), 1Z37(bs, IH)O -2-(2-formylaminothiazol-4-yl)acetamide]-5-(1
-Methyl-2-trifluoromethyl-1H! x4-
Add 4.6f of 1-riazol-5-yl)thiomethyl-6'-cephem-4-carboxylic acid and stir at the same temperature for 1 hour.
I had a hard time. Next, 78% of water was added to the reaction solution, and after concentration and washing with ethyl acetate, the pH was adjusted to 2.8. The precipitated crystals were washed several times with water and dried to give 7-[2-chloromethinone-2-
(2-aminothiazol-4-yl)acetamide]-
3-(1-methyl-2-trifluoromethyl-I H-
1,3,4-triazol-5-yl)thiomethyl-3
-Pale brown crystals of cephem-4-carboxylic acid 2.091F
I got it.

After dissolving this in saturated sodium bicarbonate hydroxide solution, HP
-20 column for purification to obtain the sodium salt.

7-[2-rialomethelene-2-(2-aminothiazol-4-yl)acetamitoco-6-(1-methyl-2
-trifluoromethyl-1H-1,44-triazol-5-yl)thiomethyl-5-cephem-4-carboxylic acid NMRδ (d6-DMf30): A67 (F3.
! IH), 570 (qAB, J-18H2, 2H),
418 ((LAB, J-14Hz, 2B), 5
．． 17 (d, J=5Hz, IH).

5.78 (dd, J-5Hz, J=BH2, IH).

6.40 (s, IH), 6.85 (s, IH), y, 1
s (bs, 2H), 9.61 (a, J-8Hz, IH
)7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(1-methyl-
Sodium 2-trifluoromethyl-1H-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate NMRδ (d6 DMSO): A48 (qAB,
J-18H2, 2H), 3.66 (J 3H), 4.2
7 (b8, 2H).

5.00 (d, J-5Hz, IH), 5.58 (dd,
J=5H2, J-8Hz, IH), 6.40(El, I
H).

6.82 (B, iH), 7.15 (bs, 2) J), 9
．． 51(d, J-8H2, IH) Example 44 02H Hiruya HO 9) (7-amino-3-(2
-carbamoylmethylthio-1,5,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-amino-3-(I H-1,2,3
Using 613 μl of 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid, the same procedure was carried out. ) acetamide] -3-
700 ml of (I H-1,2,3-triazol-4-yl)thiomethyl-5-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(I H
-1,2,5-triazol-4-yl)thiomethyl-
6-cephem-4-carboxylic acid NMRδ (d4-DMeO): 168 (qAB,
J-18H2, 2H), 197 (qAB, J-1
3Hz, 2H), 5.20 (d, J-5H2, IH),
5.79 (d'd, J=5H2゜J-8H2, IH),
7.06 (El, IH), 7.09 (e, 1H), 8.
51 (s, IH), 9.68 (d, J-8Hz, IH)
, 12.48 (bs, 1H) -2-trifluoromethyl-1H-1,3,4-triazol-5-yl)thiomethyl-6-cephem-4-carboxylic acid, 7-(2-chloromethylene-2-(2-formyl) aminothiazol-4-yl)acetamide]-3-(I
H-1,2,3-triazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid 14. Using Oj', the same operation was performed to obtain 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-(I H-1,2,3-triazole- 4-
yl)thiomethyl-3-cephem-4-carboxylic acid ao
62 and its sodium salt were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(I H-1,2
,3-)riazol-4-yl)thiomethyl-3-cephem-4-carboxylic acid NMRδ((16-DMgO)
: l 67 (qAB, J-18H2, 2H),
3L96 (qAB, J-13Hz, 2H), 5
．． 19 (d, J-5H2, IH), 5.74 (dd
, J-5Hz.

J=8H2,IH), &43(a,iH), &90(s
.

11), 7.33 (bs, 2H), 7.90 (bs, I
H).

9.61 (d, J-8Hz, IH) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(I H-1,2,3-triazole-4 -yl)thiomethyl-3-cephem-4-carboxylic acid sodium NMRδ (d6-DMeO): 5.45 (bs,
2I(), &85(qAB,,T-13H2,2H),
4.99 (d, J-5Hz, 14), 5.55 (dd,
J-5Hz, J-8H2゜IH), 6.40(s, IH
), 6.81 (s, 1H).

7, 14 (bs, 2H), 7.24 (s, IH), 9
．． 50((1,J-8)1z,in) Application Example Representative examples of the β-lactam derivatives and non-toxic salts thereof of the present invention were tested for antibacterial activity.

Antibacterial activity is determined by the minimum inhibitory concentration (MCC) (unit μ2/-
), and the measurement is performed using the method prescribed by the Japanese Society of Chemotherapy Revision Committee for Minimum Inhibitory Concentration Measurement Method [Chemotherapy (chem
29, No. 1, pp. 76-79 (1981)).

The results of the antibacterial activity measurement are shown in Table 1 below.
Compounds are indicated by example numbers. The numbers in parentheses are the numbers in the example.

Table 1 (M Engineering C) Table 1 (M Engineering C) Continued Table 1 (M Engineering C) Continued [Effects of the Invention] As explained in detail above, the β-lactam derivative of the present invention has particularly positive It is useful and has excellent antibacterial activity against bacteria and β-lactomase producing bacteria.

Patent applicant Hirodo Nakamoto, Sagami Chuo Chemical Research Institute Agent, Akito Inoue, Katsura Yoshimine, continuation of page 1 0 Inventor Yasuo Murakami 1-27-4 Minamidai, Seya-ku, Yokohama 0 Inventor Akira Toshioka 1-806 Mihama Higashi Nistate 14, Mihama, Urayasu City ■) Inventor: Osamu Sakuma Hino Type Misawa 1230-2 Hijikata Corp. No. 306 @ Inventor: Etsuko Kojima 4749-83 Kurohama, Hasuda City [Phase] Inventor: Beginner Katsumi Ota, Tokyo 102 Seikaso, 2-18-1 Higashimagome, Ward Procedural amendment (voluntary amendment) June 11, 1980 Kazuo Wakasugi, Commissioner of the Patent Office 1, Indication of the case 1988 Patent Application No. 112823 2 , Title of the invention Relationship to the β-lactam derivative five amendment case Patent applicant address 1-4-5 Marunouchi, Chiyoda-ku, Tokyo Name
Sumo Central Chemical Research Institute Representative Yoshi Ninomiya Moto Nishi Shinbashi Chuo Building 602 Telephone (437)-34672 The detailed description of the invention column in the amended statement of contents is amended as follows.

(1) "Application example" on page 158, line 7 of the specification is amended to "Application example 1."

(2) Next to Table 1 on page 161 of the same document, [[Before Effects of the Invention I, insert the following statement on a new line.

Example 45 (YM (88) f-1 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid 535f was dried in THF 30 m
1 of dicyclohexylcarbodiimide was added under cooling with water, and the mixture was stirred for 2 hours.

7-amino-3-[3-hydroxy-θ-triazolo(
4,3-b')pyridazin-6-yl]thiomethyl-
3-cephem-4-carboxylic acid 58 ffr, water 60-,
It was dissolved in 20 ml of acetone and a saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 80.

The above solution was added to this solution under water cooling, and the mixture was kept at the same temperature for 1 hour.
After stirring for 0 minutes, the reaction solution was filtered and washed with p-liquid ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted to 50 with 1N hydrochloric acid, and the precipitate was washed several times with water and dried.
[2-chloromethylene-2-(2-formylaminothiazol-4-yl]acetamide]-3-[5-hydroxy-s-triazolo(4°3-b)pyridazine-6-
Yellow crystals 5371 of [yl]thiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(5-hydroxy-〇-triazolo(4,5-b)pyridazin-6-yl)thiomethyl-3 -cephem-4-carboxylic acid NMR δ (d, -DMSO): 3.74 ((JA
B, J = 18Hz.

2) 1), 4.21 (qAB, J=13H2,2H)
, 5.21 (1, J=5H2, IH), 5.8! +
(dd, J=5.8H2゜IH), 7.02(d,
J=10H2, IH), 704(B.

IH'), 7.07(s, IH), 7.68((
1, J = 10Hz.

IH'), a50(s, IH), 9.67(cL
, J=8H2゜IH), 12.44(s, IH)
, 12.73(s, 1n)(30,H (90) 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[3-hydroxy-θ-triazolo (4,3-b)pyridazine-
[6-yl]thiomethyl-3-cephem-4-carboxylic acid 502 was mixed with 25 ml of methanol and THF2 under water cooling.
The mixture was added to a mixed solvent of 2.5 d of 5-2 water and 45 d of concentrated sulfuric acid, and then stirred at room temperature for 1.5 hours.

Next, the reaction solution was poured into ice water,
After adjusting the pH to 8 with concentrated aqueous ammonia, the mixture was washed with ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, p
H50, all precipitates, washed with water, dried, 7-[2-
Chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3-hydroxy-8-triazolo(4,5-1))pyridazin-6-yl]thiomethyl-5-cephem-4- Yellow crystals of carboxylic acid 11
I got 6ff.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[5-hydroxy-triazolo(4°3-b)pyridacy/-6-yl]thiomethyl-3 -cephem-4-carboxylic acid NMRδ (dll-DMSO): 574 (qAB,
J=18Hg.

2H), 4.20(qAB, J=13Hz, 2H
), 5.19(d, :f=5Hz, 11), 5
．． 79((1(1,, r=5.8Hz, 1H), &
39(s, IH), 6.84(s, IH).

7.03(d, , T=1'OHz, IH'l, 7
．． 17 (E+, 2H').

7.68 (d, J=10H2, IB), 9.59 (
+1. , T=8Hz, IH), 12.72(s,
IH) (91) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[3-hydroxy-day-triazolo(4,3-b)pyridazin-6-yl ] Thiomethyl-3-cephem-4-carboxylic acid was suspended in water, dissolved in a 4% aqueous sodium hydroxide solution to pH &5, purified by applying to an HE-20 column, and lyophilized to obtain 7-[2-chloromethylene -2-(2-aminothiazol-4-yl)acetamide]-3-[3-hydroxy-8-triazolo(4,3-b)pyridazine-6
-yl]thiomethyl-3-cephem-4-carboxylic acid disodium was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[3-hydroxy-6-triazolo(4,3-b)pyridazin-6-yl]thiomethyl-5- Cephem-4-carbo/acid disodium Decomposition point: 200°C or higher NMR δ (46-DMSO): 4.15 (d, ,
r==12Hz, ui).

4.44 (d, J=12Hz, IH), 5.05
(d, J=5Hz, IH), 5.58 (da,
J=5.8H2, iH).

1'59 (e, IH), 6.82 (s, IH),
7.01 (d.

J=10Hz, ITJ), 7.15(s, 2H)
, 7.62 (d.

J=10Hz, IH), 9.5o(d, J=8H
z, IH) Example 46 [92) 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid 2.799% in dry THF 16-
dicyclohexylcarbodiimide 1 dissolved in and cooled with water.
．． 499 f (plus stirring for 2.5 hours).

7-amino-3-[7-methyl-tetracylo(1,5-
b) 1.981 of pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid, 34 of water, 1 of acetone
3- and saturated aqueous sodium bicarbonate solution, pH
It was set to a8.

The above solution was added to this solution under water cooling, and after stirring at the same temperature for 1 hour, the reaction solution was filtered, the filtrate was washed with ethyl acetate, the organic solvent was distilled off under reduced pressure, and 1N hydrochloric acid was added. p
Set to H3,0, wash the precipitate with water, dry the stem, 7-[2
-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[7-methyl-tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carvone Acid light brown crystals 2
．． Obtained 19t.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[7-methyl-tetracylo(1°5-b)pyridazin-6-yl]thiomethyl-3-cephem -4-carboxylic acid NMRδ (d@-DMSO): 249(s, 3H
'), 573 (qAB, J = 18Hz, 2H),
4.23 (d, J = 13Hg, IH), 4.
65(d, J==15Hz, IH), 5.21(
d, J=5Hz, IH), 5.84 (ad, J=5.8
H2, IH), 7.04 (s, IH'), 7.07 (s
, IH).

a50 (s, 2H), 9.67 (d, J=8H2, IH
).

12.44(s, IH) 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(7-methyl-tetracylo(1,5-b)pyridazine-6 -yl]thiomethyl-3-cephem-4-carpropanic acid 21y
under ice-cooling, methanol 11Tnt, THFl 1.
l, water 1.1! I11! , concentrated sulfuric acid and 1.94 ml of a mixed solvent, and then stirred at room temperature for 2 hours.

Next, the reaction solution was mixed with ice water 100+II7! After adjusting the pH to 8 with concentrated ammonia water, the solution was washed with ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted with 1N hydrochloric acid.
3.0, remove the precipitate, wash with water, dry, 7-[2-
Chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(nia-methyl-tetrazolo(1,5-b)pyridazin-6-yl)thiomethyl-
Light brown crystals of 3-cephem-4-carboxylic acid 1.69
I got f.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[7-methyl-tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem- 4-carboxylic acid NMRδ(d@-DMSO): 2.39(s,
3H), 172 (qAB, , r=18Hz, 2
H), 4.22 (d, J=15Hz, IH),
4.65 ((1, J=13Hz, IH), 5.19
(d, J=5Hg, IH), 5.79 (dd,
J=5.8Hz.

IH), 439(s, IH), 6.84(e,
IH), 7.15 (B, 2H), a49 (s,
IH), 9.58 (a, J=8Hz, IH) (95) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(nia-methyl-
Tetrazolo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution, purified by HP-20 column, lyophilized, and 7-[2 -chloromethylene-2-(
2-aminothiazol-4-yl)acetamide]-3
Yellow amorphous crystals of sodium -(7-methyl-tetracylo(1,5-b)pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[7-methyl-tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem- Sodium 4-carboxylate NMR δ (d6-DMSO): 2.37 (day, 3H
), ! L37 (d.

J217H2,1,H), 566(d-, J:17H2
, IH).

4.31 (eL, J=12Hz, jH), 4.5
8((1, J=j2Hz, IH), 5.07((1
, J=5H2, IH), 5.61(ad, , T=5
．． 8Hz, IH), 6.39(e, IH).

6.82 (e, IH), 7.14 (bs, 2H)
, &45(llI.

IH'), 9.50 (d, J=8Hz, IH) Example 47 (96) 10.7f of 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid dissolved in THF 60- Then, under water cooling, dicyclohexylcarbodiimide 5.6
8 f k was added and stirred for 2 hours.

7-amino-3-[pyrido(2,1-c]]s-triazol-5-yl]thiomethyl 3-cephem-4-carboxylic acid 7.26 f!, 146 f! of water, 56 f of acetone, and saturated aqueous sodium bicarbonate solution Dissolved in pH 7.3
And so.

Add this solution to the above solution under water cooling. After stirring at the same temperature for 1 hour, the reaction solution was filtered by FT filter, and the reaction solution was washed with total ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted to 50 with 1N hydrochloric acid, and the precipitate was washed with water and dried to give 7-[2
-thalolomethylene-2-(2-formylaminothiazol-4-yl]acetamide]-3-[pyrido(2,1
-o') a-triazol-5-ylcothiomethyl-3
-Pale brown crystals of cephem-4-carboxylic acid 11.45f
I got it.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[:pyrido(2,1-c)θ-triazol-5-yl]thiomethyl-3-cephem-4 -Carboxylic acid NMRδ (d6-DMEIO'): 171 (qA
B, J=I BHz.

2H), 4.16(b8.2H), 5.20((1
, J=5Hz.

IH), 5.76((1(1, J=5.8H2, IH
), 7.0-7.4 (m, 4H), 7.79 (d
, J=9Hz, IH).

a51 (s, 1B), 9.44 (e, IH),
9.66 (eL.

J-8Hz, IH), 12.45(bs, IH'
) mat (98) To a mixed solvent of methanol 126- and THF 84-, phosphorus oxychloride 42TRt was added dropwise while stirring with water cooling, and to this solution was added 7-[2-chloromethylene-2-(2-formylaminothiazole-4 -yl)acetamide]-3-
[Pyrido(Otsu1-c)s-) 13ff of lyazole-5-ylcothiomethyl-3-cephem-4-carboxylic acid was added, and the mixture was stirred at the same temperature for 1.5 hours.

Next, the reaction solution was poured into 200ml of ice water, and the pH was adjusted to 7.3.
After adjustment, the mixture was washed with ethyl acetate.

Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted to 3 with 1N hydrochloric acid.
The precipitate was washed with water and dried to give 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)].
acetamido]-3-[pyrido(2,1-c)s-)lyazole-5-ylcothiomethyl-3-cephem-4-
9.22 fe of light brown crystals of carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-[pyrido(2,1
-a') e-triazol-5-ylcothiomethyl-3
-cephem-4-carboxylic acid NMRδ ((ill-DM80'): 170(qA
B, J = 17Hz.

2H), 4.15 (be, 2H), 5.19 (d, J=
5H2゜IH'), 5.73((L(1,J=5,8H
2, IH), 6.42 (s, IH), A36 (s, IH)
), 7.09 (d, J=7Hz, IH'), 7.18 (
bs, 2H'), 7.32 (da, J=7,9H2,I
H), 7.79 (d, J=9H2, IH).

9.45 (s, IH), 9.59 (d, J=8Hz, I
H) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamitoco-3-[pyrido(2
, 1-c') θ-triazol-5-yl]thiomethyl-5-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution and purified by applying it to an HP-20 column.
Lyophilized to give 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamido]-3-[pyrido(2,1-c)S-)lyazol-5-ylcothiomethyl-3-cephem. -Pale yellow amorphous crystals of sodium carboxylate? Obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[pyrido(2,1
-a) s-) Riazol-5-ylcothiomethyl-3-
Sodium cephem-4-carboxylate decomposition point = 175-185°C NMR δ (d6-DMSO): 4.3B (q4B,
J = 12Hz, 2H), 5.00(+1.,
T=5Hz, IH'), 5.55 (ad.

J=5.8Hz, IH), A40(s, IH),
/L82 (s, IH), 7.1~7.4 (m,
4H), 7.68 (a, J=9H2, IH), 9
．． 37 (8, IH), 9.50 (d, J=8Hz,
11H) Example 48 (100) 8-carboxy-6-mercapto-tetrazolo(1,5
-b) Pyridazine λ572.10 typhosphate buffer (
pH &5) 117d and sodium bicarbonate &28'r
was added and dissolved by stirring at 30 to 40°C.

Then, 7-amitusephalosboranic acid 424 S'i
In addition, the mixture was stirred at 60°C for 3 hours. Insoluble matter in the reaction solution After separating each house, the pH was adjusted to 2.8 under water cooling, the precipitate was collected, washed with water, dried, and 7-amino-3-(8-carboxy-
Brown crystals of tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid 4
．． I got Of.

7-7mi/-3-[8-carboxytetrazolo(1,
s -b ) pyridazin-6-yl]thiomethyl-3-
Cephem-4-carboxylic acid NMRδ (OF+1000D
): A94 (qAB, J=17H2゜2H'),
4.47 ((1, J=14H2, IH'), 5.2
5 (a.

J=14Hz, 1B), 5.40(s, 2H),
8.29 (s.

IH) (24) + (100) (101) 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid 535f was dried in THF 50 d
Dissolve K and dicyclohexylcarbodiimide 2 under water cooling.
．． 859' and stirred for 2 hours.

7-amino-3-[8-carboxycotetrazoo (t
5-b') Pyridazin-6-yl]thiomethyl-
3-cephem-4-carboxylic acid 4,09 f k water 64
ml, acetone, and saturated aqueous sodium bicarbonate solution to make pHal.

The above solution was added to this solution under water cooling, and after stirring at the same temperature for 1 hour, the reaction solution was filtered through p-filter, and the p-liquid was washed with ethyl acetate. After distilling off the organic solvent under reduced pressure, p
H2,6, precipitate tp collected, washed with water, dried, 7-[2
-Chloromethylene-2-(2-formylaminothiazol-4-yl]acetamido]-3-[8-calphoquitutetrazolo(+, 5-b)pyridazin-6-yl]
'8 color crystals of thiomethyl-3-cephem-4-carboxylic acid5. I got qav.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(8-carboxy-tetracylo(1,5-b)pyridazine-6
-yl]thiomethyl-3-cephem-4-carboxylic acid NMRδ(d, -DMSO'): 572((IAB,
J=18Hz, 2H), 4.20(+1., T
=13H2,IH'), 4.62(d.

, 1 = 1AT++*, lft ), 5711(+
1. ．． 1-111a, II+).

5.84 (cud, J=5.8H2, IH), 7.
04 (B, IH), 7.06 (s, IH'),
a03 (s, IH), EL50 (s, IH'),
9.68 (d, J=8Hz, IH).

l5L45(s, IH) 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[8-carboxy-tetracylo(1,5-b)pyridazine-6-
yl]thiomethyl-3-cephem-4-carboxylic acid5.
Of, under water cooling, methanol 25-1THF 25m
The mixture was added to a mixed solvent of e, water Z5- and concentrated sulfuric acid 4.3-, and then stirred at room temperature for 1.5 hours.

Next, the reaction solution was poured into 250 ml of ice water, adjusted to pH 7.0 with concentrated ammonia water, and washed with ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted with 4N hydrochloric acid.
2, 5, wash the precipitate with water, dry it, 7-[2-
Chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-carboxy-tetracylo(1,5-1+')pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid brown crystals of 4.1
7 f'i-obtained.

7-[2-chloromethylea2-(2-aminothiazol-4-yl)acetamide]-3-[8-carboxy-tetracylo(i,s-b)pyridazin-6-yl]thiomethyl-3-cephem- 4-Carboxylic acid NMR δ(a, -aMso): 571 (qAB, J
=18Hz.

2H), 4.20 (d, J = 13H2, IH')
, 461 (d.

J=13H2, IH), &17(d, J=5Hz, IH
).

5.80 (cla, J=5.8Hz, IH), &38(
e, IH'), 6.83 (s, IH), 7.16 (s,
2H), &07(B, IH), 9.59(d, J=8H
g, IH) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-
Carboxy-tetracylo(1,5-b)pyridazine-6
-yl]thiomethyl-3-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution,
Purified by column purification, lyophilized, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-5-[8-carboxy-tetrazo R(1,5
-b) Disodium pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylate was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-carboxy-tetracylo(1,5-b)pyridazin-6-yl]thiomethyl-3-cephem- Disodium 4-carboxylate Decomposition point: 200°C or higher NMR δ (a, -DMSO): 4.27 (cl,
J: 13Hz, IH), 4.56(a, J=13H
z, IH), 5.05 (d.

J=5Hz, IH), 5.58(ad, J=5.
8H2, IH), 6.39(s, IH), 6.8
1 (s, IH), 7.14 (bc+, 2H), 7.
45 (e, IH), 9.51 (a, J = 8H2, in) Example 49 Hs (104) 7-amitusephalosboranic acid &801 and 2,4-dihydro-4-methyl-3H-1, 2゜4-triazole-3-thione 2.88 f Total anhydrous acetonitrile 81-
Boron trifluoride ethyl ether complex compound 14
．． 14d'! j and stirred at 50-55°C for 1.5 hours.

Next, while cooling with water, 40 Wtt of water was added, the pH was adjusted to 3 with concentrated ammonia water, and the mixture was stirred at the same temperature for 30 minutes. The precipitate was collected, washed with water, dried, and 7-amino-3-(4-methyl-
A light brown powder of 5.33 f'j of e-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.

7-amino-5-(4-methyl-8-triazole-3
-yl)thiomethyl-6-7femu-4-carboxylic acid NMRδ(D,0-NaHOO,): A40(d,
J=18H2゜IH), X70(d, J=13
H2, 1H), 173(e.

3H), 586 (d, J=18Hz, IH), 4
．． 31 (d.

J=13Hz, IH), 5.01((1,:f=5
Hz, IH).

5.39 (d, J=5Hz, IH), a51 (s
, IH) (24) -1-(104) (105) 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid a401F in anhydrous THF 47-
Dissolve dicyclohexylcarbodiimide 4 under water cooling.
．． 51fi was added and stirred for 2 hours.

7-amino-3-(4-methyl-day-triazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid 5
．． 149 to water 102 II! 7! , dissolved in 59 ml of acetone and saturated aqueous sodium bicarbonate solution, pH 7.0
And so.

The above solution was added to this solution under water cooling, and after stirring at the same temperature for 1 hour, the reaction solution was filtered, and the p solution was washed with ethyl acetate. After distilling off the organic solvent under reduced pressure, p
H50, wash the precipitate with water, dry, 7-[2-
Chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(4-methyl-5-
) lyazol-3-yl)thiomethyl-3-cephem-
A light brown powder z902 of 4-carboxylic acid was obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-(4-methyl-8-triazol-3-yl)thiomethyl-3-
Cephem-4-carboxylic acid NMR δ (d6-DMso): 557 (B, 3H),
3.69 (qAB, J=18Hz, 2H'), 4.1
4(qAE, J=13I(Z, 2H), 5.18(d
, J=5H2, IH).

5.81 (da, J=5.8Hz, IH), 7.04 (
8, IH), 7.07 (s, IH), 8.50 (e,
1H), EL57(s, IH), 9. /+7((1,J
=8I(z, IH), 12.4(s, 1H) uct 7-[2-chloromethylea2-(2-formylaminothiazol-4-yl)acetamide]-5-(A-methyl-8- Triacy A, -5-(l)thiomethyl-3-cephem-4-carboxylic acid aO at room temperature,
The mixture was added to a mixed solvent of 44% methanol, 44% TI (F44), 44% water, and 8.07% concentrated sulfuric acid, and stirred at the same temperature for 2 hours.

Next, the reaction solution was poured into 220ml of ice water, adjusted to pEaD with concentrated aqueous ammonia, and washed with ethyl acetate. Next, after distilling off the organic solvent under reduced pressure, the pH was adjusted to 50 with 4N hydrochloric acid, and the precipitate was removed, washed with water, and dried. yl)acetamido]-1-(4-methyl-e-)lyazole-3
A light brown powder 5801 of (-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(4-methyl-8
-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid NMR δ(a, -DMso): 557(s, 3H),
! L6B (qAB, J=18Hz, 2H), 4
13 (qAB, J=13H2,2H'), 5.16
((1, J=5Hz, IH).

5.77 (da, J=5.8Hz, IH), 63
9 (s, II), ta4 (e, IH), 7.1
6 (be, 2H), &57 (s, IH), 91
60(Li, J=5Hz, IB) (107) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(4-methyl-e
-) lyazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution, purified by applying it to a UP-20 column, and lyophilized.
-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide:)-3-(4-methyl-5
-) Pale yellow amorphous crystals of sodium lyazol-3-yl]thiomethyl-3-cephem-4-carboxylate were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(4-methyl-day-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid sodium decomposition Point: 160-165°C NMR δ (d, -DMSO): 547 (q AB,
J = 17 Hz.

2H), 3.57 (s, gu), 4.20 (qA
B, J=1! IHz, 2H), 4.99(d,
J=5HI! +, II (), 5.59 (da, J
=5.8H2, IH), 6.40(s, IH).

&82(e, IH), 7.15(be, 2H),
&52(s.

IH)-9,50(d*J=8HZ,IH
) Example 50 Co, H (108) (to9) 10.7 f of 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid was dissolved in THF 60-, and dicyclohexyl was dissolved under water cooling. Carbodiimide 5.
68 f was added and stirred for 2 hours.

7-Amino-3-[s-)riazolo(4,3-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid 7.289 k Water 146-, Acetone 56-
and dissolved in saturated aqueous sodium hydrogen carbonate solution, pH 7,
It was set as 8.

The above solution was added to this solution under water cooling, and after stirring at the same temperature for 1 hour, the reaction solution was filtered and the furnace solution was washed with ethyl acetate. Then, after distilling off the organic solvent under reduced pressure, p
H3.0, remove precipitate eP, wash with water, dry, 7-[2
-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[s-)riazolo(4,3-b)pyridazin-6-yl]thiomethyl-3
-Pale brown crystals of cephem-4-carboxylic acid 11.21f
I got it.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-5-[θ-triazolo(4,3-1))pyridazin-6-yl]thiomethyl-3-cephem- 4-carboxylic acid NMRδ (d6-DMS□): A70 (qAB,
J=18H2,2H), 4.37((IAB, J:14
H2, 2H), 5.19 (d, J=5Hz, IH)
, 5.80 (da, J=5.8Hz, IH), 7.
05 (e, IH), 7.07 (s, IH).

7.26(d, J=10Hz, IH), &20(
d, J=10H2, IH), a51(s, IH), 9
．． 36(s, IH).

9.67 (d, J=8Hz, IH), 12j17 (bs
, IH) To a mixed solvent of methanol 108- and THF 72 d, while water-cooled and stirring, 7-[2-chloromethylene-2-(2-formylaminothiazole-4 -yl)acetamide]-
3-[s-triazolo(4,s-b)pyridazine-
6-yl]thiomethyl-3-cephem-4-carboxylic acid 11,19? was added and stirred at Fil temperature for 2 hours.

Next, the reaction solution was poured into 200 m of ice water, and pl (
After adjusting the temperature to 75%, the solution was washed with ethyl acetate.

Next, after distilling off the Arumaki solvent under reduced pressure, the pH was adjusted to 50 with 1N hydrochloric acid, and the precipitate was removed. 7 houses were washed with water, dried, and 7-[2-chloromethylene-2-(2-aminothiazole-4-yl acetamide]-3-[s-)riazolo(4,3-b
) pyridazin-6-yl]thiomethyl-6-cephem-
7.65 f of pale brown crystals of 4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-)riazolo(4,s-b)pyridazin-6-yl]thiomethyl-3-cephem-4 -Carboxylic acid BIMRδ (d6-DMSO): A69 (qAB,
J = 18ELz, 2H), 4.36(qAB,
J=14Hz, 2H), 5.44(d, J=5
Hz, IH), 5.76 (dd, J=5.8Hz
, IH), 6.38 (s, IH), 6.84 (m, IH
).

7.16 (bs, 2H), 726 (d, J=10
Hz, IH).

a20 (d, J = 10Hz, IH), 9.55
(B, IH).

9.58(d, J=8Hss, IH) (111) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[111-)riazolo(4,3- 1) ) Pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid? , dissolved in a saturated aqueous sodium bicarbonate solution, purified by applying to an HP-20 column, lyophilized, and 7-[2-chloromethylene-2-(2
-aminothiazol-4-yl)acetamide]-3-
Light brown amorphous crystals of sodium [:s-)riazolo(4°3-b)pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylate were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-6-[day-triazolo(4,3-b]]pyridacy:/-6-yl]thiomethyl 6-cephem- Sodium 4-carboxylate Decomposition point: 200°C or higher NMR δ (d@-DMSO): 146 (qAB,
J = 17Hz.

2H), 439((JAB, J=13H2,2H'
), 5.031 ((1, J=5H2, IH), 5.
57 (d, d, J=5.8Hz, 1.H:), 6
．． 39 (s, IH'), 6.82 (s, IH).

7.16 (M, 2H), 724 (a, J=10H
z, IH).

a14(d, J=10Hz, IH), 9.50(
(1, J=8Hz, IH), 9.53(s, IH
) Example 51 (112) 1Q, 7t of 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid was dissolved in THF 60-, and dicyclohexylcarbodiimide 5.6 was dissolved under water cooling.
89'c was added and stirred for 2 hours.

7-amino-3-[8-amino-tetracylo(1,5-
'b) Pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid z61 was added to 350 fnt of water, 250 fnt of acetone, 562 fnt of triethylamine and 0 fnt of charcoal (2,81 ft of sodium hydride).

Washed with ethyl acid. Next, the organic solvent was distilled off under reduced pressure, the pH was adjusted to 5.5, the insoluble matter was separated in a furnace, the pH was adjusted to 50, the precipitate was washed with water, dried, and 7-[2-chloromethylene-2
-(2-formylaminothiazol-4-yl)acetamide]-3-[8-amino-tetracylo(1,5-b
) Pyridazine-6-ylcothiomethyl-3-cephem-
532 g of light brown crystals of 4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[8-amino-tetracylo(1°5-b)pyridazin-6-yl]thiomethyl-3-cephem -4-carboxylic acid NMR δ (+14-DMSO): 166 (qAB,
J=18H2゜2H), 4.30((LAB, J=
13Hz, 2E'), 5.17 (1, J=5Hz, IB
), 5.78 (da, J=5.8Hz, IH), &3
3 (s, IH), 7.04 (s, IH).

7.07 (s, IH), 7.96 (bθ, 2H), a5
0(s.

Hr), 9.65 (a, J=8Hz, IH), 12.4
8(bs, IH) 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamido]-3-(8-amino-tetracylo(1,5-b)pyridazin-6-yl ]Thiomethyl-3-cephem-4-carboxylic acid 540
511:1 under ice cooling, methanol 26d% THF 26-
1 In addition to a mixed solvent of 2.6 d of water and 4.68 d of concentrated sulfuric acid,
Stir for 1.5 hours at room temperature.

Next, the reaction solution was poured into ice water, and the pH was adjusted with aqueous ammonia.
! LO, remove precipitate eF, wash with water, dry, 7-[2-
Chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(8-amino-tetracylo(
1,5-b) Pyridazin-6-yl]thiomethyl-3-
4.22 of light brown crystals of cepham 4-cargonic acid were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-amino-tetracylo(1,5-'b)pyridazin-6-yl]thiomethyl-3-cephem -4-carboxylic acid NMR δ (a, -pMso): 569 (qAB, J
-18H2°2H), 4. ．． 50 (qAB, J==
13Hz, zn), 5.18(a, J=5Hz,
IH), 5.78(dd, J=5.8Hz, I
H), &32(s, IH), &39(s, IH
).

6.84 (s, 1) 1), 7.16 (bs, 2H
), 7.96 (bs, 2H), 9.58 (d,
J=BHz, IH) (115) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(8-amino-tetrazoo(1,5-b)pyridazine- Dissolve 7-[2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamide]-3-,
Pale yellow amorphous crystals of sodium (s-amino-tetracylo(1,5-b)pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[8-amino-tetracylo(1,5-b'1 pyridazin-6-yl)thiomethyl-3-cephem -4-Sodium carboxylate NMRδ (68-DMSO'): 54B (qAB,
J=18Hz, 22(), 4.33(qAB, J
=12Hz, 2H), 5.04(d, J=5.T
! z, IH'), 5.59(ad, J=5.8H
z, 11(), &5B(e, IB'), 6.5
9(s, IH).

ll, 82(s, IH), 714(1) day, 2H), 7
．． 95 (1+ days.

2H), 9.50 (d, J=8Hz, IH) Example 52 Co, H (116”), (117) 2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid 11. 20f'!j THF
65-, 5.97f of dicyclohexylcarbodiimide was added under water cooling, and the mixture was stirred for 1.5 hours.

7-amino-3-[pyrido(2,1-c) s-triazole-3-ylcothiomethyl-3-cephem-4-
Carboxylic acid aofi water 110ml 1. It was dissolved in 50 Wt of acetone and sodium hydrogen carbonate, and the pH was adjusted to 7.7.

This solution K was added with the above solution under water cooling, and at the same temperature, 1.5
After stirring for an hour, the reaction solution was filtered through P filter, and the P solution was washed with ethyl acetate. Next, the pH was adjusted to 4.9 with hydrochloric acid, the insoluble matter was adjusted to pH 3.3, and the precipitate was washed with water and dried.
[2-chloromethylene-2-(2-formylaminothiazol-4-yl]acetamide]-3-[pyrido(2
, 1-c) Brown amorphous crystals 1[15f'i of s-triazol-3-ylcothiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-[pyrido(2,1-C)s -)lyazol-3-ylkothiomethyl-3-cephem-4- Carboxylic acid NMR δ (ad-DMSO'): 576 (qAB,
J=18H2゜2H'), 4.06(s, 2H)
, 5.14 (a, , r=5Hz.

IH), 5.77 (ad, J=5.8Hz, IH), 7
．． 06 (S, IH), 7.08 (8, IH), l46
(d-a, J=7.9Hz, IH), 7.82(a,
J-9Hz, IH).

8.46 (d, J=7Hz, IH), a51 (s, IH
).

9.69 (eL, , r=8Hz, IH), 12.45 (
e, IH) 7-[2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3
-[pyrido(2,1-c)s-triazol-3-ylcothiomethyl-3-cephem-4-carboxylic acid 10.1
methanol 4 (1 m, THIF4
It was added to a mixed solvent of Dd, water 4- and concentrated sulfuric acid z5-, and stirred at room temperature for 2 hours and 20 minutes.

Next, the reaction solution was poured into 370 d of ice water, and the pH was adjusted to 0 with an aqueous solution of 10% sodium hydroxide. p take,
Wash with water, dry, 7-[2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamide]-6-[
7.69 f of yellow crystals of pyrido(2,1-c) s-)riazol-3-ylcothiomethyl-3-cephem-4-carboxylic acid were obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[pyrido(2,1
-c) s-triazol-5-ylcothiomethyl-3-
Cephem-4-carboxylic acid NMRδ (d6-DMEIO'): 3.76 (
qAB, J = 18Hz.

2H), 4.06CB, 2H), 5.15(cl, J=
511゜IH), 5.74 (d4.J=5.aH2,I
H), &42 (s, IB), &86 (s, IH), 7.
f2(t, J=7HL l11), 7.48(+1+1
．． J=7.9H2, IH).

7.82 (d, J=9Hg, IH), a47 (d, J=
7Hz, IH), 9.62 (d, J=8H2, IH)H
9) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[pyrido(2,1
-c) s-) Riazol-3-4l]thiomethyl-3-cephem-4-carboxylic acid was dissolved in a saturated aqueous sodium bicarbonate solution and purified by applying it to a UP-20 column.
lEl rearranges to form 7-(2-chloromethylene-2-(2-
aminothiazol-4-yl)acetamide]-3-(
Total sodium pyrido(2,1-c)g-triazol-3-ylcothiomethyl-3-cephem-4-carboxylate was obtained.

7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[pyrido(2,1
-c) s-triazol-3-ylcothiomethyl-3-
Cephem-4-carbonate sodium decomposition point: 220℃ or higher 11MRδ (dls-DMBO): 545 (qAB,
, T=17Hz, 2H'), 409(d, J=1
2Hz, IH), 4.24(d, J, = 12H2
,1B), 4.97(d, ,T==5Eg, 2H
).

5.58 (da, , T=5.8H2, IB), 44
0 (s, IH), 483 (s, 1 to'), 7.0
8 (t, X=7Hz, 1H), 7.17 (s, 2
H), 7.45 (ad, J=7.9HE, IH)
, 7.80((1, J=9Hg, 11(), 1l
L48 (tl, J=7Hz, IH), 9.52 (
+i, J=8Hz, IH) Example 53 Co, H (120) 02Na (121') Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminotheazol di-4- yl)acetamido]-3-(4-methylthiadiazol-5-yl)
Sodium thiomethyl-3-cephem-4-carboxylate (isomer A) ft was obtained.

NMRδCeLa-DMBO): 2-55(s, 5
H), 542 (qARJ=18HJ 2H), 4.
55 ((IAB, J=13Hz.

2H), 5.05 (+1.:r=5H2,IH), 5.
62 (A4°IH), 7.15 ('be, 2H), 9.
50(d,:f=8Hm.

IH) Example 54 not (122) 01Na (123) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide] -3-(1, Sodium 2<5-thiadiazol-3-yl)thiomethyl-6-cephem-4-carboxylate (isomer A) was obtained.

NMRδ((14-DMSO): X46(QAB, J
=17HJ 2H), 4.48((lAJ3.J=
14H2,2H), 5.05(d, J=5Hz, I
H), 5.60(dd, J=81(z.

J=8Hg, IH), 6.42(e, 111),
6.84 (e.

1H 7.14 (BS, 2B), 9.03 (S, IH)
.

9.48 ((1, J = 8 Hz, IH) Example 55 00, H (124) Hat a 01Na (125) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2- aminothiazol-4-yl)acetamide]-3-(2-hydroxycarbonylmethyl-1,
Disodium 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(A6-DMBO): A48(qAB,
J=18Hz, 2H), A57(s, 2B),
4.44 ((IAB, J-=13Hz.

2H), 5.03(a, , T=5Hz, In),
5.61 (da.

J=5Hg, :I=8Hz, 1B), A42(s
, IH).

6.84 (e, 1n), 714 (bs, 2H),
9.48 ((1°J=8Hg3.IH) Elemental analysis value: (4gH11N6C1NalO@EI4
・Calculated value as H2O 0:3! L94H:L37
N: 1! 1.19 analysis value C; 3596 H: 2.7
2 N; 1503 Example 56 0EC1 00,H (126) 02Na (127) 7-[2-chloromethylene-2-(2-aminothiazol-4-yl) Acetamide:]-3-(5-(N-p-hydroxyphenyl)
Sodium carbamoylmethyl-4-methyl-1,3-thiadiazol-2-yl)cothiomethyl-3-cephem-4-carboxylate (isomer Alft was obtained.

NMRδ((111-DMSO): 2.28(s,
3H), 543 (CIAB.

J=17Hz, 2H), 3L75 (8, 2H), 4.3
2 (qAB, J=11Hg, 2H), a02(d, J=
5Ha, IH), 5.57 (ad, J=5Hz, J=8
Hz.

IH), 6.43 (g, IH), &70 (d, J=9
H2゜2H), 6.84 (s, 1H'), 712 (bs
, 2H).

7.38 (+1. J=9Hz, 2H), 9.20 (s
, IH).

9.46 ((1,, r=8Hsg, IH), 9.97(
bs, IH) Elemental analysis value: 0211H1 Goose N60tN
Calculated value as aO11S4・H2O C:43t42
H:xL36 N:1t6B analysis value 0:4[L20
1(:!L42 N:1α74 Example 57 aat CO鵞H (128) 002N& 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide] Sodium -3-(1,3-thiazol-2-yl)thiomethyl-5-cephem-4-carboxylate (isomer A) was obtained.

)IMRδ(d6-DMEIO): ! L45(q),
B, J=17Hz, 2H), 4.41 (qAB
, J=12H2,2H), 5.04(d, J=
5Hz, II(), 5.60(da, J=5Hz
.

J=8Hz, IH), &43(s, 1)i),
485 (s.

IH), 7.15 (bs, 2H), 7.66 (d
, J=4H2゜IH), 7.74(a, J=4H
2,1 engineering 1), 9.48 ((1°J=8H2,111
1) Example 58 (130) Hct (131) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(4-methyl -5-oxo-6-hydroxy-4,5-dihydro-t,2,4-) riazine-
Sodium 3-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ (d6-DMSO): 5.4 (m, 2H
), ! L61 (s.

3H), 4.3(m, 2H), 5.05(d,
J=5Hz, IH), 5.60(d, (1, J=
5HB, J=9) (z, IH).

6.46(s, IH), &87(s, IH),
717(be.

2H), 9.49(ti, J=8Hz, II()
Example 59 cmct C0 February (132) OHO/= 1 C! 02Na (133') Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamido]-3-(2-methyl-1,54-thiadiazole) Sodium -5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMR δ (a, -DMSO): 2.47 (θ, sH
), 548 (qAB, J=17Hz, 2H”),
4.29 (qABt J=13Hz, 2H), 5.0
4 (d, J=5H1?, IH).

5.62 (deL, J=5Hz, J=8Hz
), 443 (e.

IH), 486 (s, IH'), 7.15 (be, zF
).

9.48 (d. Sodium thiazol-4-yl)acetamido]-3-(3-methyl-2,4-oxadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ (C14-DMBO): 2.31 (s,
5H), 549 (qAB, J=18Hz, zn),
t3ycqhB, J=15Hz, 2H), 5.
07(d, J=5Hz, IH).

5.64 (deL, J=5Hz, J=5H2,11
H), 6.42(e, 1B), &86(s, I
H), 7.17 (bs, 2H).

9.51 (d, J=7Hz, IH) Example 61 Co, H (136) 02Na (157) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazole- 4-yl)acetamido]-3-(4-methyl-1,3-oxazole-2
-yl)thiomethyl-6-cephem-4-carbonate sodium porcelain (isomer) was obtained.

NMRδ(d6-DMEIO): 2.07(d,
J=2Hz, SR).

3.43 (QAB, J=18H2,2H), 42
9 (bl!i.

2H), 5.04(+1. :f=SHtt,, I
H), 561 (dd.

J=5Hz, J=BHz, IH), 6j! 3(8,
IH).

6.83 (s, 1B), 7.16 (bg, 2H)
, 7.83 (+1°J=2Hz, IH), 9.4
9 (+1., T = 8 Hz, iH) Example 62 (30,H (13B) C02Na (139) Sodium aminothiazol-4-yl)acetamido]-3-(1-methyl-1,3,5-ylazol-2-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) child.

NMRδ(d6-DMEIO): 2.51 (e,
5H), 5.49(qAB, J = 18H2,2H
), 4.37 (qAB, J=15Hz, 2H
), 5.07 (C1, J=5Hz, IB).

5.64((L(1, J=5Hz, J=5H2, IH
), 6.42(s, 1B), &B6(8, IE'
), 7.17 (bs, 2H).

9.51 (a, J=7Hz, in) Example 63 mat (140) (i41) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl) ) Sodium acetamido]-3-(2-hydroxy-1,3,5-)lyazol-5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ (d6-DMSO): 5.56 (qAB,
2H), 4.70 (qAB, 2H), 5.12
(+1. J==5H2, IH).

! 11.65 (tia, J=sug, J=8Hz,
IH), 6.42 (g, 1111), 484 (e,
11(), 7.15(ba, 2H), 9.63((1,
J=8HK, IH) Example 64 Hct (142) (143) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-5- (5-methoxycarbonyl-4-methyl-
1,2,4-triazol-5-yl)thiomethyl-5
Sodium -cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d@-DM8o): A4B(qAB, J=
13Hz.

2H), 587 (s, 3H), 592 (s, 3H).

4.33(be, 2H), 5.05((1, J=5Hz
, IH).

561 (ad, J=8Hz, T=8Hg, IH), 1
44 (s, IH), 484 (s, IH), 7.15 (b
e, 11).

9.48 (d, J=8Hz, 1a) Example 65 C! 0. H (144) 02Na (145) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-5-methoxy Carbonyl-
1,2,4-triazol-5-yl)thiomethyl-3
Sodium -cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMSO): 147 ((JAB
, J=16H2,2H), 581(s, 3B),
586 (e, 3H), 4.34 (bs, 2H),
5.05 (d, J=51 (z, IH), 5.6
3 (dd, J:8Hz, J=8H2, IR), 7
．． 44 (Ill.

IFI), 7.86(s, H(), &15(bs
, 2H).

9.49 ((1, J=8Hz, I H') Example 6
6 co, H (146) (!O1N& (147) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-(3- Carboxy-1-methyl-1,2,
4-) Riazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid disodium (isomer A) was obtained.

NMRδ(d@-DMSO): 144 ((IAB
, J=20HJ2H), 571 (is, 3H),
4.50 ((JAB, J=12685(s, IH
), 7.14 (be, 2H), 9.48 (d,
J=8Hz, IH) Example 67 (148) HC4 Using the same method as Example 6, 7-[2chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[1 -(2-carboxy)ethyl-1,2,
Disodium 3,4-tetrazol-5-yl]thiomethyl-5-cephem-4-carboxylate (tetramer A) was obtained.

NMIIδ(a6-DMSO): 2.42(t,
, T=7H2,2B).

! L4B (qAB, J=17Hz, 2H), 4.
34 (be.

2H), 4.34(t,; f=7Hts, 2H'), 5
．． 05(d.

J = 5Hz, I H), 5.63 (d, d, J = 5
Hz, J = 8H2, IH), 6.43(e, IL()
, &85 (s, 1B), 7.14 (be, 2B), 9.
52 (d, J = 8H7°I H') Example 68 nct (150) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide] Sodium -'3-[1-(2-methoxycarbonyl)ethyl-1,2,A4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (external form A) was obtained.

NMRδ (+16-DMBO): 3.02 (t,
J=7Hz, 2H).

A50 (qAB-J=17Hz, 2H), 3.6
1 (s, 3B), 4.35 ((IAB, J=:
12Hz, 2H'), 4.48(t, ,T==7
H2, 2B), s, o4 (a, :J=5Hz, I
H), 5.62 (d4. J=5Hz, J=8H
z, 'jH).

fh45 (a, IH), 6.85 (s, IH),
7.15 (bs.

2H), 9.49 (a, J = anz, tH) Example 69 oin (152) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl) ) Sodium acetamido]-3-(3-methylthio-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(d6-DMBO'): 2.63(θ,
3H), 544 (qAB, J-=18E1g, 2H
'), 4.46 (qAB, J=12Hg, 2H)
, 5-05(d, :f=51Hs, fl.

5.61 (d, cJ,, J=!Mlz, J=8
Hz, IH).

6.43(s, IH), 6[4(s, IH),
7.15 (be.

21), 9-49 (d, J=8Hz, tn),
Among them, Example 70 CO鵞H (154') HO1 01Na (155) Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)thiomethyl-3-(3 Sodium -methoxy-1,2,4-thiadiazole-5-,yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was administered.

NMRδ(d6-DMBO): A46(qAB,
, r=17Hz, 2H), 4.00(e, 3H)
, 4.43((IAB, J=12H2,2H),
5.05 (d, J=5Hz, IH), 5.61 (
da, J=5Hz, J=8Hz, IH), A4
5 (a.

1B), 6.85 (a, jE), 715 (bs,
2H).

9.49 ((1, J = 8Hg, IH) Practical Example 71 Co, H (15/+) 02Na (157) Following the same method as Example 6, 7-[2-chloromethylene-2-(2- Sodium aminothiazol-4-yl)acetamide]-!1-(3-ethyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(+18-DMBO): 1.28(t,
J=8Hz, 3H).

2.88(q, J=8Hz, 2H), A48(q
AB, J=17 Hw, 2B), a, s O(
qAB, J=12RZ, 2H').

5.07 (+i, J=5H2, IH), 5.63 (d,
d,,T=5H2,J=8)is,IH),6.44
(e, 1B').

1h86 (e, IH), 7.17 (bs, 2H), 9.
51 (d.

J=8Hz, IH) Elemental analysis: (4gH16N60tNa0484 ・2
Total % as H20, (IN, O: 55.85 H:
X 34 N: 13.93 analysis value 0:3, 7
4 H; 507 N: 1593 Example 72 Hat 1 (158) (159) Following a method similar to Example 6, 7-[2-chloromethylene-2-(2-7minothiazol-4-yl)acetamide ]-3-(1-(N-meth)oxy)carbamoylmethyl-1,2°'5.4-tetrazol-5-yl]thiomethyl was obtained.

NMFIδ (a, -DM13o): 549 (qAB
, J = 17 Hz.

2B), 563 (B, 31N), 4.30 (qAB
, J=12Hz, 2H), 498(s, 2H'
), 5.04 (cl, J=5Hz, IH), 5
．． 65(d, eL, J=5Hz, J=8H2゜I
H'), &45(s, IH'), 6.87(s,
in).

7.17(be, 2H), 9.51((1, J=8
H2,1F) Elemental analysis OI@EH uniform 06NaO@s
, a Calculated value as 2H10 C; 3546 H; 52B N: 1ρ51 Analysis value a; s s 18 H;
525 N: 1a56 Example 75 klO1 (160) (161') Following the same method as Example 6, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3- CI-(2-carbamoyl)ethyl-1,
2,54-tetrazol-5-yl]thiomethyl-6-
Sodium cephem-4-carboxylate (isomer A) 1f
I got t.

NMRδ ((1g-DM80): 2.73 (t,
, T=7H2,2H).

551 ((IAB, 2H), 4.37(bs, 2
H), 444 (t, J='7Hm, 2H), 5.05
(d, J=5Hz, IH), 5.63(ad,, T=5
H2, J=8Hg, 1F).

&44 (s, IH), 6.86 (a, 11), /L94
(1) E+.

IH), 7.15 (be, 2H), 7.62 (bs, 1
)1').

9,50 (d, J=8Hg, IH) Elemental analysis value:
Calculated value as O,,II,,N,01a05S,-2F20 0: 543 l H: 6N: 20.0
1 analysis value C: 3444 H: 515 N: 19.63
Example 74 HC3t 1 (162) (163) Following a method similar to Example 6, 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide]-3-[1-(N -methyl)carbamoylmethyl-1,2,A4-tetrazol-5-ylcothiomethyl-3-cephem-4-carbonyl sodium (isomer A
) was obtained.

NMRδ (dg-DM80): 2.67 (d,
J==5Hz, 3111).

A52 (qAB, J=17H2,2H), 4.3
3 ((IAB.

J=13Hg, 2H), 5.08(d, J=5H
g, IH).

5.11 (e, 2H), 5.66 (dcl,
J=511z, J=8H2, In), 6.46(e,
IH), 6.89 (g, In'l.

7.20 (bs, 2H), EL58 (a, J=5
)1m, IB).

9.54 (+1. J=8Hz, IH) Elemental analysis value:
Calculated value as C1@H17C6NaO5S3・2H10 0:34.31 H:536 N:2[L[11 Analysis value 0:3A, 66 E:510 G:19.9B Application example 2 The present invention in each of the above embodiments The antibacterial activity of the compound was tested using the same method as in Application Example 1.

The results are shown in Table 2 below. Note that the number in parentheses in the Example number button is the number of the compound in the corresponding example.

Table 2 Proceedings Amendment (Spontaneous amendment September 25, 1980 Manabu Shiga, Commissioner of the Patent Office 1, Indication of the case Patent Application No. 112823 of 1988 2)
, Title of the invention β-lactam rust conductor 3, Relationship to the amended sound person case Patent applicant address 1-4-5 Marunouchi, Chiyoda-ku, Tokyo Name Name
Representative Yoshiki Ninomiya, Sagami Central Chemical Research Institute Address: 5-15-8 Nishi-Shinbashi, Minato-ku, Tokyo Section 4 of the detailed description of the invention in the description of contents of the Z amendment is amended as follows.

(1) Add the following statement on a new line after Table 2 on page 79 of the written amendment dated June 11, 1988.

[Example 75 (164) (165) Following the same method as in Example 6, 7-(2-chloromethylene-2-(2-aminothiazol-4-yrunacetamide)-5-(1-(N,N -dimethylcarbamoyl)
Sodium methyl-1゜2,5.4-tetrazol-5-yl)thiomethyl-6-cephem-4-carboxylate (
Isomer A) was obtained.

NMRδ(as-DMSO): 2.91 (s,
5H), 3.12 (s.

5H), 5.50 ((LAB, J=18Hz, 2H
), 4.52 (qAB, J=j 5LIZ, 2H)
, 5.07 ((1, J=5 HZ-I H) #
5.50 (s, 2”) * 5-65 (dl
-J=5Hz, J=8t(z, IH), &47
(s, IH).

6.90 (s, IH), 7.19 (be, 2
H), 9.52 (d.

J=8Hz, IH) Elemental analysis value: 01gH1gNg 04NaOsSx
' Calculated value as I H2O C: 36.45 H: &
3B N:2α14 analysis value 0:54.66 H:51
0 N: 19.99 Example 76 (166) aat (167) Following the same method as Example 6, 7-(2-chloromethylene-2-(2-aminothiazol-4-ylnoacetamide)-5-( Sodium f-(2-N,N-dimethylcarbamoyl)ethyl-1,2j,4-tetrazol-5-ylcothiomethyl-5-cephem-4-carboxylate (isomer A) was obtained.

NMRδ(a6-DMEIOJ: 2.80 (s,
5H), 2.96 (θ, 3H).

3.00 (t, J=7Hz, 2H), 3.49
(qAB, J=17Hz, 2H)p 4.55
(qAB, J=12 Hz, 2H).

4.44 (t, J=7H2,2H), 5.05
(d, J=5H2゜J=IH), 5.62 (+1+1. J=5Hz, △
8Hz, IH), &44(s, IH), 6.
86 (s, IH), 712 (be, 2H).

9.45 (d,, J=8Hz, IH) Elemental analysis value; C! ,,1B,,N,0tNaO,Sl・I H
, O Calculated value 0:57.55 H: &62 N:
19.69 Analysis value 0:36.97) 1144 N:
Example 77 (169) According to the same method as in Example 6, 7-(2-chloromethylene-2-(2-7minothiazol-4-yl)acetamide)-s-(1-(2-N, N-dimethylaminosulfonylonethyl-1,2,5,4-tetrazole-5-
Sodium ylcothiomethyl-3-cephem-4-carboxylate (isomer A) was obtained.

NMRδ (d, -hDMSOn: 2.79 (s
,bH)t i5 ((1,,,#J=18IIz,2
H), &72 (t, J==7Hz, 2H).

a, 56 (q AB , J = 12 HZ# 2
H), 4-68 (tt J =7Hz, 2H),
5.05 (d, J=5Hz, IH), 5.62 (a
d, J=5Hz, J=13H2, IH), 6.45
(s.

IH), 6.87 (s, IH), 7.14
(bs, 2) tl.

9.47 (d, J=8Hz, iH) Elemental analysis value: OH@Hll N@Ol'Na0684-18
Calculated value as 20 C25! L75H: 3.45N
:1864 analysis value 0:! lA45H: 3.17N
:1a55 Example 78 (170) (17S) Following the same method as Example 6, 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide)-5-(1-(2 -methoxy)ethyl-1,2,
Sodium-5-ylcothiomethyl-3-cephem-4-carboxylate (isomer A) was added to 5,4-tetrazo.

NMRδ(as-DMSO): 3.25 (θ,
5H⇠3.46 (qA>J=18H2,2H), 3.
74 (tt J=5H2, 2H).

4.55 (qAB, , r=12Hz, 2H),
4.46 (t,, r=5H2,2H), 5.03
(d, J=5)1z, IH), 5.61(dd,
, T:5H2, J = BHz, IH), 6.44
(s.

I H), 6.85 (s, I H), 7.12 (b
s, 2H).

9.44 ((1, J=8Hz, I J elemental analysis value:
CtsHtsNsotNa05s3・2H20 Analysis value 0:55.04 Hl, 59 N:1&16 Calculated value 0:35.29 H:5. ! i4 N:1a13
Example 79 ○HO1 02H (172) According to the same method as in Example 6, 7-(2-chloromethylene-2-(2-aminothiazol-4-yrunacetamide)-3-methoxymethyl-5-cephem- Sodium 4-carboxylate (isomer A) fc was obtained.

NMRδ ((16-DMSO): 5.16 (θ
, 5H), 3.44 (qAB.

J=18Hz, 2H), 4.25 (qAB, J
=12Hz.

2H), 4.84 (a, J=5Hz, IH)
, 6.57 ('tIH), &95 (s, IH
), 7.15 (be, 2H).

EL2B (a, J=8'Hz, IH) Example 8
0 (174) C02H Following a method similar to Example 40, 7-[2-chloromethylene-2-(2-aminothiazol-4-yrunacetamide)-5-(2-inquiturinium]methyl-3-
Cephem-4-carboxylate (isomer A) was obtained.

Melting point = 180°C (decomposition) NMRδ (d, -DMSO): 537 (qAB
, J=18H2,2H).

5.12 (d, J=5H2, I H), 5.22
((1, J-=15Hz, I H), 5.67 (d
4. , T=5H2, J=8Hz, 1HJ.

5.82 (a, J=1 5Hz, IH), 6.55
(s, IH).

6.78 (s, I H), 7.14 (be, 2
H), acl-8,6 (m, 5H), 9.45 (a
, J=7H2,I H), 9.52(a,, T=8Hz
, I H), 1 0.26 (e, I H) Example 81 acz Following a method similar to Example 40, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide) -5-(2<6-cyclobenteno-1-pyridinium)methyl-5-cephem-4-carboxylate (isomer A) was obtained.

Melting point: 190-195°C (decomposition) NMRδ (a@-DMSO): 2.25 (be
, 2H), 5.11 (a.

J=18Hz, IH), 3.12(bt, 2t(
), 5.591H), 5.47 (d, J=14
H2, IH), 5.66 (dd, J:=5Hz,
J=8H2, IH), 6.58 (s, IH).

7.15 (BS, 2H), 7.8? (ad,
J=6Hz, T=8Hz, IH), 8.54
(d, J=8Hz, IH), 9.28((1,
J=6Hz, IH), 9.51 ((1, J=8
Hz, IH) Example 82 (178) HO2 Following a method similar to Example 40, 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide)-5-(4-(2 -Sulfoethyl)-1-pyridiniumcomethyl-3-cephem-4-carboxylate monosodium salt (isomer A, Jk was obtained.

Melting point = 205-210°C (decomposition) NMRa (as -DMBO): 2.84 (b
t, 2H), 101 (d.

, T=18H2, 1H), A17 (bt, 2J,
553 (d,, T:1 8H2), 4.99 (d, J
=15Hz, IH).

5.11 (d, J=5Hz, IH), 5.6
1 (cl, J=15J=H2,IH), 5.67 (ad, J=5H2,B
Hz, IH).

△ 6.56 (s, I H), 6.80 (s, I
H), 715 (bs.

2H), ELO6 (d, ;f=6Hz, 2H),
9.50 (d.

J=6Hz, 2H), 9.54 ((1, J=8'H2
, I H) Example 83 HOt (18o)002H HOt Following a method similar to Example 4a, 7-[2-chloromethylea-2-(aminothiazol-4-yl λ acetamide]-3-(4-carbamoyl- 1-Viridinicum λ methyl-5-cephem-4-carboxylate (JI form A
) was obtained.

Melting point near 6-78℃ (decomposition NMRδ(dg-DMBO): 5A O(m,
2H 5.70 (m.

2H), 6.56 (s, 1H n, 6.80 (s, j
H), 7.14 (bs, 2H), A24 (b8.
IH), A44 (d, J=7Hz, 2H), A
73 (bg, IH), 9.52 (d.

;f=BHz, IH), 9.62 (d, I=7H*,
2H) Example 84 (182)C02H Following a method similar to Example 40, 7-(2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide)-1-(4-hydroxymethyl -1-pyridinium)methyl-3-cephem-4-carboxylate (isomer A) was obtained.

Melting point = 89-91°C (decomposition) NMRδ (a, -DMSO): i05 (d,
J==18H2, IH).

155 (d, , T=18H2, IH), 4-8
0 (s, 2H).

5.10 (d, , T=14Hz, IH), 5
．． 12 (a, J=5H2, I H), 5.62 (
(1, J=1 4H2, 1H).

5,68 (dd, J=5 Hz, J==13 H
z, 1H) e 6.36 (s, I J, 6.8
0 (s, I H), 7.15 (bIl!, 2
H).

ao5 (d, J--6Hz, 2H), 9. ! +2(d
, J=6Hz.

2H), 9.52 (a, J=8H2, IH) Example 8
5 Following a method similar to Example 40, 7-(2-chloromethylene-2-(2-7minothiazol-4-yl)acetamide)-! 1-(4-carbamoylmethylthio-1-
Viridinium trimethyl-5-cephem-4-carboxylate (isomer A) was obtained.

Melting point = 154-157°C (decomposition NMRδ(da-DME30): !LO5(d,
J=18Hz, IH).

155 (d, J=18H2, IH), 4.09
(s, 2H 几4.90 (d, J=15H2,I
H), 5.67 (dd, J=5Hz, J=8
Hz, IH), 6.56 (s, IH), 6
．． 80 (s, IH), 7.15 (bs, 2H)
), 7.40 (BS, IH).

7.99 (d, J=7Hz, 2H), 8.00
(BS, IH).

9.16 (d, J=7Hz, 2H), 9.54 (d
, :f=8Hz.

1H Example 86 (18υ Following the same method as Example 40, 7-[2-chloromethylene-2-(2-aminothiazol-4-yl)acetamide)-5-(4-methoxycarbonylmethylthio-
1-pyridiniumtumethyl-6-cephem-4-carboxylate (isomer A) was obtained.

Melting point: 120-122°C (Decomposition NMRδ ((16-DMSO): 505 ((1,
J=18H*, I Hl.

162 (cl, J=18Hz, IH), 3.71
(s, 5H).

4.59 (s, 2H), 4.92 (d, ,r
=14Hz, IH).

5.10 (+1. J=5H2, IH), 5.4
9 (d, J=14Hz-IH) e 5-66
(dd-J = 5 Hz, J = 8 HZeI H),
l,, 57 (s, IH), &80 (s, IH), 7
．． 15 (d, , T = 7Hz, 2H), 9.51
((1,, T = 8H2, IH) Example 87 (188) Co, H cHaz Following the same method as Example 40, 7-[2-chloromethylene-2-(2-aminothiazol-4-yrunacetamide) )-5-(4-carpoxymethylthio-1-pyridinium)methyl-6-cephem-4-carboxylate monosodium salt (isomer A) was obtained.

Melting point = 73-75°C (decomposition) NMRδ (d4-DMSO): 3.05 (d, J
=18Hz, IH).

&52 ((1, J=18Hz, IH), 3.7
2 (s, 2H).

4.88 (cl, J=14H2, IH), 5.
11 (a, J=5Hz, IH), 5.45
(d, J=14 Hz, I HJ.

5.66 (del, , T=5Hz, J=8Hz,
1H), 6.36 (s, IH), 6. BO(s,
IH), 7.17 (bs, 2H).

7.82 (d, J=7Hz, 2H), 9.02 (d
, J=7Hz.

2H≠9.56 (d, , T=8H2, I HJ) The compounds of the present invention in each of the above Examples were tested for antibacterial activity in the same manner as in Application Example 1 (1:f).

The results are all shown in Table 5 below. In addition, the number in parentheses in the section of Example number is the number of the compound in the corresponding example.

Claims (1)

[Claims] 1. The following general formula I: [wherein R represents a substituted or unsubstituted thiazolyl group or furyl group, R1 represents hydrogen or a halogen atom,
R2 represents )10 gene atoms, a lower alkoxycarbonyl group, a hydroxyl group or a carboxymethylmercapto group, and Y
In the formula % formula %, R3 represents a -R5 or -B-R5 group, where IR5 means a containing heterocyclic residue, and R4 is hydrogen, a ring-forming cation, or a carboxylic acid Yato group. (representing a group), where R1 is hydrogen and R2 is a halogen atom, Y is a β-lactam derivative or a nontoxic salt thereof further represented by the formula.